Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®) - National Cancer Institute

21/5/2014 Childhood Acute Lymphoblastic Leukemia Treatment (PDQ) - National Cancer Institute
National Cancer Institute at the National Institutes of Health
Childhood Acute Lymphoblastic Leukemia Treatment (PDQ)
Health Professional Version

Last Modified: 05/02/2014
Table of Contents
General Information About Childhood Acute Lymphoblastic Leukemia (ALL)

Incidence and Epidemiology
Anatomy
Risk Factors for Developing ALL
Down syndrome
Inherited genetic polymorphisms
Prenatal origin of childhood ALL
Clinical Presentation
Diagnosis
Overall Outcome for ALL
Current Clinical Trials
Risk-based Treatment Assignment

Introduction to Risk-based Treatment
Prognostic Factors Affecting Risk-based Treatment
Patient characteristics affecting prognosis
Leukemic cell characteristics affecting prognosis
Response to initial treatment affecting prognosis
Prognostic (Risk) Groups
Childrens Oncology Group (COG) risk groups
Berlin-Frankfurt-Mnster (BFM) risk groups
Prognostic (risk) groups under clinical evaluation
Treatment Option Overview for Childhood ALL

Phases of Therapy
Sanctuary Sites
Central nervous system (CNS)
Testes
http://www.cancer.gov/cancertopics/pdq/treatment/childALL/HealthProfessional/page1/AllPages/Print 1/135
Treatment for Newly Diagnosed Childhood ALL

Standard Treatment Options for Newly Diagnosed ALL
Remission induction chemotherapy
Response to remission induction chemotherapy
Postinduction Treatment for Childhood ALL

Standard Postinduction Treatment Options for Childhood ALL
Consolidation/intensification therapy
Maintenance therapy
Treatment options under clinical evaluation
CNS-directed Therapy for Childhood ALL

Intrathecal Chemotherapy
CNS-directed Systemic Chemotherapy
Cranial Radiation
CNS Therapy for Standard-risk Patients
CNS Therapy for High-risk Patients
CNS Therapy for Patients With CNS Involvement (CNS3 Disease) at Diagnosis
Presymptomatic CNS Therapy Options Under Clinical Evaluation
Toxicity of CNS-directed Therapy
Acute/subacute toxicities
Late-developing toxicities
Postinduction Treatment for Specific ALL Subgroups

T-Cell ALL
Treatment options
Treatment options under clinical evaluation for T-cell ALL
Infants With ALL
Treatment options for infants with MLL translocations
Treatment options for infants without MLL translocations
Treatment options under clinical evaluation for infants with ALL
Adolescents and Young Adults With ALL
Treatment options
Treatment options under clinical evaluation for adolescent and young adult patients with ALL
Philadelphia Chromosomepositive ALL
Treatment options
Treatment options under clinical evaluation for Philadelphia chromosomepositive ALL
Treatment of Relapsed Childhood ALL

Prognostic Factors After First Relapse of Childhood ALL
Site of relapse
Time from diagnosis to relapse
Patient characteristics
Risk group classification at initial diagnosis
Response to reinduction therapy
Cytogenetics/genomic alterations
Immunophenotype
Standard Treatment Options for First Bone Marrow Relapse of Childhood ALL
Reinduction chemotherapy
Postreinduction therapy for patients achieving a second complete remission
Standard Treatment for Second and Subsequent Bone Marrow Relapse
Hematopoietic Stem Cell Transplantation for First and Subsequent Bone Marrow Relapse
Components of the transplantation process
Intrathecal medication after HSCT to prevent relapse
Relapse after allogeneic HSCT for relapsed ALL
Treatment of Isolated Extramedullary Relapse
CNS relapse
Testicular relapse
Treatment Options Under Clinical Evaluation for Relapsed Childhood ALL
Trials for ALL in first relapse
Trials for ALL in second or subsequent relapse
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General Information About Childhood Acute Lymphoblastic Leukemia

(ALL)
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood
cancer, including ALL, has been slowly increasing since 1975.[1] Children and adolescents with cancer
should be referred to medical centers that have a multidisciplinary team of cancer specialists with
experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team
approach incorporates the skills of the following health care professionals and others to ensure that
children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and
quality of life:
Primary care physician.

Pediatric surgical subspecialists.
Radiation oncologists.
Pediatric medical oncologists/hematologists.
Rehabilitation specialists.
Pediatric nurse specialists.
Social workers.
Child life professionals.
Psychologists.
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive
care for children and adolescents with cancer.)
Guidelines for cancer centers and their role in the treatment of pediatric patients with cancer have been
outlined by the American Academy of Pediatrics.[2] Because treatment of children with ALL entails
complicated risk assignment and therapies and the need for intensive supportive care (e.g., transfusions;
management of infectious complications; and emotional, financial, and developmental support),
evaluation and treatment are best coordinated by pediatric oncologists in cancer centers or hospitals with
all of the necessary pediatric supportive care facilities. It is important that the clinical centers and the
specialists directing the patients care maintain contact with the referring physician in the community.
Strong lines of communication optimize any urgent or interim care required when the child is at home.
Dramatic improvements in survival have been achieved in children and adolescents with cancer.[1,3,4]
Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[3,4] For ALL, the 5-
year survival rate has increased over the same time from 60% to approximately 90% for children
younger than 15 years and from 28% to approximately 70% for adolescents aged 15 to 19 years.[1,3-5]
Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects
may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of
Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of
late effects in childhood and adolescent cancer survivors.)
Incidence and Epidemiology
ALL is the most common cancer diagnosed in children and represents approximately 25% of cancer
diagnoses among children younger than 15 years.[3,4] ALL occurs at an annual rate of 35 to 40 cases per
1 million people in the United States.[3,4,6] There are approximately 2,900 children and adolescents
younger than 20 years diagnosed with ALL each year in the United States.[6,7] Over the past 25 years,
there has been a gradual increase in the incidence of ALL.[3,4,8]
A sharp peak in ALL incidence is observed among children aged 2 to 3 years (>90 cases per 1 million per
year), with rates decreasing to fewer than 30 cases per 1 million by age 8 years.[3,4] The incidence of ALL
among children aged 2 to 3 years is approximately fourfold greater than that for infants and is likewise
fourfold to fivefold greater than that for children aged 10 years and older.[3,4]
The incidence of ALL appears to be highest in Hispanic children (43 cases per 1 million).[3,4,6] The
incidence is substantially higher in white children than in black children, with a nearly threefold higher
incidence of ALL from age 2 to 3 years in white children than in black children.[3,4,6]
Anatomy
Childhood ALL originates in the T- and B-lymphoblasts in the bone marrow (see Figure 1).
Figure 1 . Blood cell dev elopm ent. Different blood and im m une cell lineages,
including T- and B-ly m phocy tes, differentiate from a com m on blood stem cell.
Marrow involvement of acute leukemia as seen by light microscopy is defined as follows:
M1: Fewer than 5% blast cells.

M2: 5% to 25% blast cells.
M3: Greater than 25% blast cells.
Most patients with acute leukemia present with an M3 marrow.
Risk Factors for Developing ALL
Few factors associated with an increased risk of ALL have been identified. The primary accepted risk
factors for ALL include the following:
Prenatal exposure to x-rays.
Postnatal exposure to high doses of radiation (e.g., therapeutic radiation as previously used for
conditions such as tinea capitis and thymus enlargement).
Genetic conditions that include the following:

Down syndrome.
Neurofibromatosis.[9]
Shwachman syndrome.[10,11]
Bloom syndrome.[12]
Ataxia telangiectasia.[13]
Inherited genetic polymorphisms.
Down syndrome
Children with Down syndrome have an increased risk of developing both ALL and acute myeloid leukemia
(AML),[14,15] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and
2.7% by age 30 years.[14,15]
Approximately one-half to two-thirds of cases of acute leukemia in children with Down syndrome are
ALL, and about 2% to 3% of childhood ALL cases occur in children with Down syndrome.[16-18] While
the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years
(median age, 1 year),[19] ALL in children with Down syndrome has an age distribution similar to that of
ALL in nonDown syndrome children, with a median age of 3 to 4 years.[16,17]
Patients with ALL and Down syndrome have a lower incidence of both favorable (t(12;21) and
hyperdiploidy) and unfavorable (t(9;22) or t(4;11) and hypodiploidy) cytogenetic findings and a near
absence of T-cell phenotype.[16-19] Approximately 50% to 60% of cases of ALL in children with Down
syndrome have genomic alterations affecting CRLF2 that generally result in overexpression of this gene.
[20-22] CRLF2 genomic alterations are observed at a much lower frequency (<10%) in children with B-
precursor ALL who do not have Down syndrome.[22-24] It does not appear that genomic CRLF2
aberrations in patients with Down syndrome and ALL have prognostic relevance.[21] However, IKZF1
gene deletions, observed in up to 35% of patients with Down syndrome and ALL, have been associated
with a significantly worse outcome in this group of patients.[21]
Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired
JAK2 mutations,[20,21,25-27] a finding that is uncommon among younger children with ALL but that is
observed in a subset of primarily older children and adolescents with high-risk B-precursor ALL.[28]
Almost all Down syndrome ALL cases with JAK2 mutations also have CRLF2 genomic alterations.[20-22]
Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free
survival in children with Down syndrome and ALL,[21,26] but more study is needed to address this issue
and the prognostic significance of IKZF1 gene deletions.
Inherited genetic polymorphisms
Genome-wide association studies show that some germline (inherited) genetic polymorphisms are
associated with the development of childhood ALL.[29] For example, the risk alleles of ARID5B are
strongly associated with the development of hyperdiploid B-precursor ALL. ARID5B is a gene that
encodes a transcriptional factor important in embryonic development, cell typespecific gene
expression, and cell growth regulation.[30,31]
Prenatal origin of childhood ALL
Development of ALL is in most cases a multi-step process, with more than one genomic alteration
required for frank leukemia to develop. In at least some cases of childhood ALL, the initial genomic
alteration appears to occur in utero. Evidence in support of this comes from the observation that the
immunoglobulin or T-cell receptor antigen rearrangements that are unique to each patients leukemia
cells can be detected in blood samples obtained at birth.[32,33] Similarly, in ALL characterized by specific
chromosomal abnormalities, some patients appear to have blood cells carrying at least one leukemic
genomic abnormality at the time of birth, with additional cooperative genomic changes acquired
postnatally.[32-34] Genomic studies of identical twins with concordant leukemia further support the
prenatal origin of some leukemias.[32,35]
There is also evidence that some children who never develop ALL are born with very rare blood cells
carrying a genomic alteration associated with ALL. For example, in one study, 1% of neonatal blood spots
(Guthrie cards) tested positive for the ETV6-RUNX1 translocation, far exceeding the number of cases of
ETV6-RUNX1 ALL in children.[36] Other reports confirm [37] or do not confirm [38] this finding.
Nonetheless, if confirmed, it would support the hypothesis that additional postnatal genomic changes are
needed for the development of this type of ALL and that in most cases in which a leukemia-associated
alteration is present at birth, the additional leukemogenic genomic changes do not occur and no leukemia
develops.
Clinical Presentation
The typical and atypical symptoms and clinical findings of childhood ALL have been published.[39-41]
Diagnosis
The diagnostic evaluation needed to definitively diagnose childhood ALL has been published.[39-42]
Overall Outcome for ALL
Among children with ALL, more than 95% attain remission, and approximately 80% of patients aged 1 to
18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free
survivors.[43-48]
Despite the treatment advances noted in childhood ALL, numerous important biologic and therapeutic
questions remain to be answered before the goal of curing every child with ALL with the least associated
toxicity can be achieved. The systematic investigation of these issues requires large clinical trials, and the
opportunity to participate in these trials is offered to most patients/families.
Clinical trials for children and adolescents with ALL are generally designed to compare therapy that is
currently accepted as standard with investigational regimens that seek to improve cure rates and/or
decrease toxicity. In certain trials in which the cure rate for the patient group is very high, therapy
reduction questions may be asked. Much of the progress made in identifying curative therapies for
childhood ALL and other childhood cancers has been achieved through investigator-driven discovery and
tested in carefully randomized, controlled, multi-institutional clinical trials. Information about ongoing
clinical trials is available from the NCI Web site.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with
childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location,
drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
References
1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer:
challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED A bstract]
2. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment.
American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics
99 (1): 139-41, 1997. [PUBMED A bstract]
3. Childhood cancer. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics
Review, 1975-2010. Bethesda, Md: National Cancer Institute, based on November 2012 SEER data
submission, posted to the SEER web site, April 2013, Section 28. Also available online. Last
accessed April 04, 2014.
4. Childhood cancer by the ICCC. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer
Statistics Review, 1975-2010. Bethesda, Md: National Cancer Institute, based on November 2012
SEER data submission, posted to the SEER web site, April 2013, Section 29. Also available online.
Last accessed April 04, 2014.
5. Hunger SP, Lu X, Devidas M, et al.: Improved survival for children and adolescents with acute
lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J
Clin Oncol 30 (14): 1663-9, 2012. [PUBMED A bstract]
6. Smith MA, Ries LA, Gurney JG, et al.: Leukemia. In: Ries LA, Smith MA, Gurney JG, et al., eds.:
Cancer incidence and survival among children and adolescents: United States SEER Program 1975-
1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp
17-34. Also available online. Last accessed April 04, 2014.
7. Dores GM, Devesa SS, Curtis RE, et al.: Acute leukemia incidence and patient survival among
children and adults in the United States, 2001-2007. Blood 119 (1): 34-43, 2012. [PUBMED A bstract]
8. Shah A, Coleman MP: Increasing incidence of childhood leukaemia: a controversy re-examined. Br

J Cancer 97 (7): 1009-12, 2007. [PUBMED A bstract]
9. Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: a

population-based UKCCSG study. Br J Cancer 70 (5): 969-72, 1994. [PUBMED A bstract]
10. Strevens MJ, Lilleyman JS, Williams RB: Shwachman's syndrome and acute lymphoblastic
leukaemia. Br Med J 2 (6129): 18, 1978. [PUBMED A bstract]
11. Woods WG, Roloff JS, Lukens JN, et al.: The occurrence of leukemia in patients with the
Shwachman syndrome. J Pediatr 99 (3): 425-8, 1981. [PUBMED A bstract]
12. Passarge E: Bloom's syndrome: the German experience. Ann Genet 34 (3-4): 179-97, 1991. [PUBMED
A bstract]
13. Taylor AM, Metcalfe JA, Thick J, et al.: Leukemia and lymphoma in ataxia telangiectasia. Blood 87
(2): 423-38, 1996. [PUBMED A bstract]
14. Hasle H: Pattern of malignant disorders in individuals with Down's syndrome. Lancet Oncol 2 (7):
429-36, 2001. [PUBMED A bstract]
15. Whitlock JA: Down syndrome and acute lymphoblastic leukaemia. Br J Haematol 135 (5): 595-602,
2006. [PUBMED A bstract]
16. Zeller B, Gustafsson G, Forestier E, et al.: Acute leukaemia in children with Down syndrome: a
population-based Nordic study. Br J Haematol 128 (6): 797-804, 2005. [PUBMED A bstract]
17. Arico M, Ziino O, Valsecchi MG, et al.: Acute lymphoblastic leukemia and Down syndrome:
presenting features and treatment outcome in the experience of the Italian Association of Pediatric
Hematology and Oncology (AIEOP). Cancer 113 (3): 515-21, 2008. [PUBMED A bstract]
18. Maloney KW, Carroll WL, Carroll AJ, et al.: Down syndrome childhood acute lymphoblastic
leukemia has a unique spectrum of sentinel cytogenetic lesions that influences treatment outcome:
a report from the Children's Oncology Group. Blood 116 (7): 1045-50, 2010. [PUBMED A bstract]
19. Chessells JM, Harrison G, Richards SM, et al.: Down's syndrome and acute lymphoblastic
leukaemia: clinical features and response to treatment. Arch Dis Child 85 (4): 321-5, 2001. [PUBMED
A bstract]
20. Hertzberg L, Vendramini E, Ganmore I, et al.: Down syndrome acute lymphoblastic leukemia, a
highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated
JAK2: a report from the International BFM Study Group. Blood 115 (5): 1006-17, 2010. [PUBMED
A bstract]
21. Buitenkamp TD, Pieters R, Gallimore NE, et al.: Outcome in children with Down's syndrome and
acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations. Leukemia 26 (10):
22. Mullighan CG, Collins-Underwood JR, Phillips LA, et al.: Rearrangement of CRLF2 in B-progenitor-
and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet 41 (11): 1243-6, 2009.
[PUBMED A bstract]
23. Harvey RC, Mullighan CG, Chen IM, et al.: Rearrangement of CRLF2 is associated with mutation of
JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-
progenitor acute lymphoblastic leukemia. Blood 115 (26): 5312-21, 2010. [PUBMED A bstract]
24. Schwab CJ, Chilton L, Morrison H, et al.: Genes commonly deleted in childhood B-cell precursor
acute lymphoblastic leukemia: association with cytogenetics and clinical features. Haematologica
98 (7): 1081-8, 2013. [PUBMED A bstract]
25. Bercovich D, Ganmore I, Scott LM, et al.: Mutations of JAK2 in acute lymphoblastic leukaemias
associated with Down's syndrome. Lancet 372 (9648): 1484-92, 2008. [PUBMED A bstract]
26. Gaikwad A, Rye CL, Devidas M, et al.: Prevalence and clinical correlates of JAK2 mutations in
Down syndrome acute lymphoblastic leukaemia. Br J Haematol 144 (6): 930-2, 2009. [PUBMED
A bstract]
27. Kearney L, Gonzalez De Castro D, Yeung J, et al.: Specific JAK2 mutation (JAK2R683) and multiple
gene deletions in Down syndrome acute lymphoblastic leukemia. Blood 113 (3): 646-8, 2009.
[PUBMED A bstract]
28. Mullighan CG, Zhang J, Harvey RC, et al.: JAK mutations in high-risk childhood acute
lymphoblastic leukemia. Proc Natl Acad Sci U S A 106 (23): 9414-8, 2009. [PUBMED A bstract]
29. de Jonge R, Tissing WJ, Hooijberg JH, et al.: Polymorphisms in folate-related genes and risk of
pediatric acute lymphoblastic leukemia. Blood 113 (10): 2284-9, 2009. [PUBMED A bstract]
30. Papaemmanuil E, Hosking FJ, Vijayakrishnan J, et al.: Loci on 7p12.2, 10q21.2 and 14q11.2 are
associated with risk of childhood acute lymphoblastic leukemia. Nat Genet 41 (9): 1006-10, 2009.
[PUBMED A bstract]
31. Trevio LR, Yang W, French D, et al.: Germline genomic variants associated with childhood acute
lymphoblastic leukemia. Nat Genet 41 (9): 1001-5, 2009. [PUBMED A bstract]
32. Greaves MF, Wiemels J: Origins of chromosome translocations in childhood leukaemia. Nat Rev
Cancer 3 (9): 639-49, 2003. [PUBMED A bstract]
33. Taub JW, Konrad MA, Ge Y, et al.: High frequency of leukemic clones in newborn screening blood
samples of children with B-precursor acute lymphoblastic leukemia. Blood 99 (8): 2992-6, 2002.
[PUBMED A bstract]
34. Bateman CM, Colman SM, Chaplin T, et al.: Acquisition of genome-wide copy number alterations in
monozygotic twins with acute lymphoblastic leukemia. Blood 115 (17): 3553-8, 2010. [PUBMED
A bstract]
35. Greaves MF, Maia AT, Wiemels JL, et al.: Leukemia in twins: lessons in natural history. Blood 102
(7): 2321-33, 2003. [PUBMED A bstract]
36. Mori H, Colman SM, Xiao Z, et al.: Chromosome translocations and covert leukemic clones are
generated during normal fetal development. Proc Natl Acad Sci U S A 99 (12): 8242-7, 2002.
[PUBMED A bstract]
37. Zuna J, Madzo J, Krejci O, et al.: ETV6/RUNX1 (TEL/AML1) is a frequent prenatal first hit in
childhood leukemia. Blood 117 (1): 368-9; author reply 370-1, 2011. [PUBMED A bstract]
38. Lausten-Thomsen U, Madsen HO, Vestergaard TR, et al.: Prevalence of t(12;21)[ETV6-RUNX1]-

positive cells in healthy neonates. Blood 117 (1): 186-9, 2011. [PUBMED A bstract]
39. Margolin J, Rabin K, Steuber CP, et al.: Acute lymphoblastic leukemia. In: Pizzo PA, Poplack DG,
eds.: Principles and Practice of Pediatric Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams
and Wilkins, 2011, pp 518-65.
40. Chessells JM; haemostasis and thrombosis task force, British committee for standards in
haematology.: Pitfalls in the diagnosis of childhood leukaemia. Br J Haematol 114 (3): 506-11,
41. Onciu M: Acute lymphoblastic leukemia. Hematol Oncol Clin North Am 23 (4): 655-74, 2009.
[PUBMED A bstract]
42. Heerema-McKenney A, Cleary M, Arber D: Pathology and molecular diagnosis of leukemias and
lymphomas. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 6th ed.
Philadelphia, Pa: Lippincott Williams and Wilkins, 2011, pp 138-63.
43. Mricke A, Reiter A, Zimmermann M, et al.: Risk-adjusted therapy of acute lymphoblastic
leukemia can decrease treatment burden and improve survival: treatment results of 2169
unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111 (9): 4477-
89, 2008. [PUBMED A bstract]
44. Moghrabi A, Levy DE, Asselin B, et al.: Results of the Dana-Farber Cancer Institute ALL
Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 109 (3): 896-
45. Pui CH, Campana D, Pei D, et al.: Treating childhood acute lymphoblastic leukemia without cranial
irradiation. N Engl J Med 360 (26): 2730-41, 2009. [PUBMED A bstract]
46. Veerman AJ, Kamps WA, van den Berg H, et al.: Dexamethasone-based therapy for childhood acute
lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG)
protocol ALL-9 (1997-2004). Lancet Oncol 10 (10): 957-66, 2009. [PUBMED A bstract]
47. Salzer WL, Devidas M, Carroll WL, et al.: Long-term results of the pediatric oncology group studies
for childhood acute lymphoblastic leukemia 1984-2001: a report from the children's oncology
group. Leukemia 24 (2): 355-70, 2010. [PUBMED A bstract]
48. Gaynon PS, Angiolillo AL, Carroll WL, et al.: Long-term results of the children's cancer group
studies for childhood acute lymphoblastic leukemia 1983-2002: a Children's Oncology Group
Report. Leukemia 24 (2): 285-97, 2010. [PUBMED A bstract]
Risk-based Treatment Assignment
Introduction to Risk-based Treatment
Children with acute lymphoblastic leukemia (ALL) are usually treated according to risk groups defined by
both clinical and laboratory features. The intensity of treatment required for favorable outcome varies
substantially among subsets of children with ALL. Risk-based treatment assignment is utilized in children
with ALL so that patients with favorable clinical and biological features who are likely to have a very good
outcome with modest therapy can be spared more intensive and toxic treatment, while a more aggressive,
and potentially more toxic, therapeutic approach can be provided for patients who have a lower
probability of long-term survival.[1-3]
Certain ALL study groups, such as the Childrens Oncology Group (COG), use a more or less intensive
induction regimen based on a subset of pretreatment factors, while other groups give a similar induction
regimen to all patients. Factors used by the COG to determine the intensity of induction include
immunophenotype and the National Cancer Institute (NCI) risk group classification. The NCI risk group
classification stratifies risk according to age and white blood cell (WBC) count:[1]
Standard riskWBC count less than 50,000/L and age 1 to younger than 10 years.
High riskWBC count 50,000/L or greater and/or age 10 years or older.
All study groups modify the intensity of postinduction therapy based on a variety of prognostic factors,
including NCI risk group, immunophenotype, early response determinations, and cytogenetics.[3]
Risk-based treatment assignment requires the availability of prognostic factors that reliably predict
outcome. For children with ALL, a number of factors have demonstrated prognostic value, some of which
are described below.[4] The factors described are grouped into the following three categories:
Patient characteristics affecting prognosis.
Leukemic cell characteristics affecting prognosis.
Response to initial treatment affecting prognosis.
As in any discussion of prognostic factors, the relative order of significance and the interrelationship of
the variables are often treatment dependent and require multivariate analysis to determine which factors
operate independently as prognostic variables.[5,6] Because prognostic factors are treatment dependent,
improvements in therapy may diminish or abrogate the significance of any of these presumed prognostic
factors.
A subset of the prognostic and clinical factors discussed below is used for the initial stratification of
children with ALL for treatment assignment. (Refer to the Prognostic (risk) groups under clinical
evaluation section of this summary for brief descriptions of the prognostic groupings currently applied in
ongoing clinical trials in the United States.)
(Refer to the Prognostic Factors After First Relapse of Childhood ALL section of this summary for
information about important prognostic factors at relapse.)
Prognostic Factors Affecting Risk-based Treatment
Patient characteristics affecting prognosis
Patient characteristics affecting prognosis include the following:
1. Age at diagnosis.
2. WBC count at diagnosis.
3. Central nervous system (CNS) involvement at diagnosis.
4. Testicular involvement at diagnosis.
5. Down syndrome (trisomy 21).
6. Gender.
7. Race.
Age at diagnosis
Age at diagnosis has strong prognostic significance, reflecting the different underlying biology of ALL in
different age groups.[7]
1. Infants (younger than 1 year)
Infants with ALL have a particularly high risk of treatment failure. Treatment failure is most
common in the following groups:[8-11]
Infants younger than 6 months (with an even poorer prognosis for those aged 60 to 90 days).
Infants with extremely high presenting leukocyte counts.
Infants with a poor response to a prednisone prophase.
Infants with an MLL gene rearrangement.
Approximately 80% of infants with ALL have an MLL gene rearrangement.[10,12,13] The rate of
MLL gene translocations is extremely high in infants younger than 6 months; from 6 months to 1
year, the incidence of MLL translocations decreases but remains higher than that observed in older
children.[10,14] Black infants with ALL are significantly less likely to have MLL translocations than
white infants.[14] Infants with leukemia and MLL translocations typically have very high WBC
counts and an increased incidence of CNS involvement. Overall survival (OS) is poor, especially in
infants younger than 6 months.[10,11] A gene expression profile analysis in infants with MLL-
rearranged ALL revealed significant differences between patients younger than 90 days and older
infants, suggesting distinctive age-related biological behaviors for MLL-translocation ALL that may
relate to the significantly poorer outcome for the youngest infants.[15]
Blasts from infants with MLL translocations are typically CD10 negative and express high levels of
FLT3.[10,11,13,16] Conversely, infants whose leukemic cells show a germline MLL gene
configuration frequently present with CD10-positive precursor-B immunophenotype. These
infants have a significantly better outcome than do infants with ALL characterized by MLL
translocations.[10,11,13]
2. Young children (aged 1 to <10 years)
Young children (aged 1 to <10 years) have a better disease-free survival (DFS) than older children,
adolescents, and infants.[1,7,17] The improved prognosis in young children is at least partly
explained by the more frequent occurrence of favorable cytogenetic features in the leukemic blasts
including hyperdiploidy with 51 or more chromosomes and/or favorable chromosome trisomies,
or the ETV6-RUNX1 (t(12;21), also known as the TEL-AML1 translocation).[7,18,19]
3. Adolescents and young adults (10 years)
In general, the outcome of patients aged 10 years and older is inferior to that of patients aged 1 to
younger than 10 years. However, the outcome for older children, especially adolescents, has
improved significantly over time.[20-22] Five-year survival rates for adolescents aged 15 to 19
years increased from 36% (19751984) to 72% (20032009).[23-25] Multiple retrospective
studies have suggested that adolescents aged 16 to 21 years have a better outcome when treated on
pediatric versus adult protocols.[26-28] (Refer to the Postinduction Treatment for Specific ALL
Subgroups section of this summary for more information about adolescents with ALL.)
WBC count at diagnosis
A WBC count of 50,000/L is generally used as an operational cut point between better and poorer
prognosis,[1] although the relationship between WBC count and prognosis is a continuous rather than a
step function. Patients with B-precursor ALL and high WBC counts at diagnosis have an increased risk of
treatment failure compared with patients with low initial WBC counts.
The median WBC count at diagnosis is much higher for T-cell ALL (>50,000/L) than for B-precursor
ALL (<10,000/L), and there is no consistent effect of WBC count at diagnosis on prognosis for T-cell
ALL.[6,29-35] One factor that might explain the lack of prognostic effect for WBC count at diagnosis may
be the very poor outcome observed for T-cell ALL with the early T-cell precursor phenotype, as patients
with this subtype appear to have lower WBC count at diagnosis (median, <50,000/L) than do other T-
cell ALL patients.[36]
CNS involvement at diagnosis
The presence or absence of CNS leukemia at diagnosis has prognostic significance. Patients who have a
nontraumatic diagnostic lumbar puncture may be placed into one of three categories according to the
number of WBC/L and the presence or absence of blasts on cytospin as follows:
CNS1: Cerebrospinal fluid (CSF) that is cytospin negative for blasts regardless of WBC count.
CNS2: CSF with fewer than 5 WBC/L and cytospin positive for blasts.
CNS3 (CNS disease): CSF with 5 or more WBC/L and cytospin positive for blasts.
Children with ALL who present with CNS disease (CNS3) at diagnosis are at a higher risk of treatment
failure (both within the CNS and systemically) than are patients who are classified as CNS1 or CNS2.[37]
Some studies have reported increased risk of CNS relapse and/or inferior event-free survival (EFS) in
CNS2 patients, compared with CNS1 patients,[38,39] while others have not.[37,40-42]
A traumatic lumbar puncture (10 erythrocytes/L) that includes blasts at diagnosis has also been
associated with increased risk of CNS relapse and overall poorer outcome in some studies,[37,43,41] but
not others.[38,40] Patients with CNS2, CNS3, or traumatic lumbar puncture have a higher frequency of
unfavorable prognostic characteristics than do those with CNS1, including significantly higher WBC
counts at diagnosis, older age at diagnosis, an increased frequency of the T-cell ALL phenotype, and MLL
gene rearrangements.[37,40,41]
Some clinical trial groups have approached CNS2 and traumatic lumbar puncture by utilizing more
intensive therapy, primarily additional doses of intrathecal therapy during induction.[37,44]; [40][Level
of evidence: 2A] Other groups have not altered therapy based on CNS2 status.[38,45]
To determine whether a patient with a traumatic lumbar puncture (with blasts) should be treated as CNS3,
the COG uses an algorithm relating the WBC and red blood cell counts in the spinal fluid and the
peripheral blood.[46]
T esticular involvement at diagnosis
Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males, most
commonly in T-cell ALL.
In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more
aggressive initial therapy, however, it does not appear that testicular involvement at diagnosis has
prognostic significance.[47,48] For example, the European Organization for Research and Treatment of
Cancer (EORTC [EORTC-58881]) reported no adverse prognostic significance for overt testicular
involvement at diagnosis.[48]
The role of radiation therapy for testicular involvement is unclear. A study from St. Jude Children's
Research Hospital (SJCRH) suggests that a good outcome can be achieved with aggressive conventional
chemotherapy without radiation.[47] The COG has also adopted this strategy for boys with testicular
involvement that resolves completely by the end of induction therapy. The COG considers patients with
testicular involvement to be high risk regardless of other presenting features, but most other large clinical
trial groups in the United States and Europe do not consider testicular disease to be a high-risk feature.
Down syndrome (trisomy 21)
Outcome in children with Down syndrome and ALL has generally been reported as somewhat inferior to
outcomes observed in children who do not have Down syndrome.[49-52]
The lower EFS and OS of children with Down syndrome appear to be related to higher rates of treatment-
related mortality and the absence of favorable biological features such as ETV6-RUNX1 or trisomies of
chromosomes 4 and 10.[49-53] In a report from the COG, among B-precursor ALL patients who lacked
MLL translocations, BCR-ABL1, ETV6-RUNX1, or trisomies of chromosomes 4 and 10, the EFS and OS
were similar in children with and without Down syndrome.[53] Certain genomic abnormalities, such as
IKZF1 deletions, CRLF2 aberrations, and JAK mutations are seen more frequently in ALL arising in
children with Down syndrome than in those without Down syndrome.[54-58] In one study of Down
syndrome children with ALL, the presence of IKZF1 deletions (but not CRLF2 aberrations or JAK
mutations) was associated with an inferior prognosis.[58]
Gender
In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[59-61] One
reason for the better prognosis for girls is the occurrence of testicular relapses among boys, but boys also
appear to be at increased risk of bone marrow and CNS relapse for reasons that are not well understood.
[59-61] While some reports describe outcomes for boys as closely approaching those of girls,[44,62]
larger clinical trial experiences and national data continue to show somewhat lower survival rates for
boys.[23,24,63]
Race
Survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white
children with ALL.[64,65] Asian children with ALL fare slightly better than white children.[65]
The reason for better outcomes in white and Asian children than in black and Hispanic children is at least
partially explained by the different spectrum of ALL subtypes. For example, black children have a higher
relative incidence of T-cell ALL and lower rates of favorable genetic subtypes of precursor B-cell ALL.
Differences in outcome may also be related to treatment adherence, as illustrated by a study of adherence
to oral 6-mercaptopurine in maintenance therapy. In this study, there was an increased risk of relapse in
Hispanic children compared with non-Hispanic white children, depending on the level of adherence, even
when adjusting for other known variables. However, at adherence rates of 90% or more, Hispanic
children continued to demonstrate increased rates of relapse.[66] Ancestry-related genomic variations
may also contribute to racial/ethnic disparities in both the incidence and outcome of ALL.[67] For
example, the differential presence of specific host polymorphisms in different racial/ethnic groups may
contribute to outcome disparities, as illustrated by the occurrence of single nucleotide polymorphisms in
the ARID5B gene that occur more frequently among Hispanics and are linked to both ALL susceptibility
and to relapse hazard.[68]
Leukemic cell characteristics affecting prognosis
Leukemic cell characteristics affecting prognosis include the following:
1. Morphology.
2. Immunophenotype.
3. Cytogenetics/genomic alterations.
Morphology
In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having
L1 morphology, L2 morphology, or L3 morphology.[69] However, because of the lack of independent
prognostic significance and the subjective nature of this classification system, it is no longer used.
Most cases of ALL that show L3 morphology express surface immunoglobulin (Ig) and have a C-MYC gene
translocation identical to that seen in Burkitt lymphoma (i.e., t(8;14)). Patients with this specific rare form
of leukemia (mature B-cell or Burkitt leukemia) should be treated according to protocols for Burkitt
lymphoma. (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more
information about the treatment of B-cell ALL and Burkitt lymphoma.)
Immunophenotype
The World Health Organization (WHO) classifies ALL as either:[70]
B lymphoblastic leukemia.
T lymphoblastic leukemia.
Either B or T lymphoblastic leukemia can coexpress myeloid antigens. These cases need to be
distinguished from leukemia of ambiguous lineage.
1. Precursor B-cell ALL (WHO B lymphoblastic leukemia)
Before 2008, the WHO classified B lymphoblastic leukemia as precursor-B lymphoblastic

leukemia, and this terminology is still frequently used in the literature of childhood ALL to
distinguish it from mature B-cell ALL. Mature B-cell ALL is now termed Burkitt leukemia and
requires different treatment than has been given for precursor B-cell ALL. The older terminology
will continue to be used throughout this summary.
Precursor B-cell ALL, defined by the expression of cytoplasmic CD79a, CD19, HLA-DR, and other
B cell-associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of
precursor B-cell ALL cases express the CD10 surface antigen (formerly known as common ALL
antigen [cALLa]). Absence of CD10 is associated with MLL translocations, particularly t(4;11), and
a poor outcome.[10,71] It is not clear whether CD10-negativity has any independent prognostic
significance in the absence of an MLL gene rearrangement.[72]
The major subtypes of precursor B-cell ALL are as follows:
Common precursor B-cell ALL (CD10 positive and no surface or cytoplasmic Ig)
Approximately three-quarters of patients with precursor B-cell ALL have the common
precursor B-cell immunophenotype and have the best prognosis. Patients with favorable
cytogenetics almost always show a common precursor B-cell immunophenotype.
Pro-B ALL (CD10 negative and no surface or cytoplasmic Ig)
Approximately 5% of patients have the pro-B immunophenotype. Pro-B is the most common
immunophenotype seen in infants and is often associated with MLL gene rearrangements.
Pre-B ALL (presence of cytoplasmic Ig)
The leukemic cells of patients with pre-B ALL contain cytoplasmic Ig, and 25% of patients
with pre-B ALL have the t(1;19) translocation with TCF3-PBX1 (also known as E2A-PBX1)
fusion (see below).[73,74]
Approximately 3% of patients have transitional pre-B ALL with expression of surface Ig

heavy chain without expression of light chain, C-MYC gene involvement, or L3 morphology.
Patients with this phenotype respond well to therapy used for precursor B-cell ALL.[75]
Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression,

generally with FAB L3 morphology and a translocation involving the C-MYC gene), also
called Burkitt leukemia. The treatment for mature B-cell ALL is based on therapy for non-
Hodgkin lymphoma and is completely different from that for precursor B-cell ALL. Rare
cases of mature B-cell leukemia that lack surface Ig but have L3 morphology with C-MYC
gene translocations should also be treated as mature B-cell leukemia.[75] (Refer to the PDQ
summary on Childhood Non-Hodgkin Lymphoma Treatment for more information about the
treatment of children with B-cell ALL and Burkitt lymphoma.)
2. T -cell ALL
T-cell ALL is defined by expression of the T cellassociated antigens (cytoplasmic CD3, with CD7
plus CD2 or CD5) on leukemic blasts. T-cell ALL is frequently associated with a constellation of
clinical features, including the following:[17,29,62]
Male gender.
Older age.
Leukocytosis.
Mediastinal mass.
With appropriately intensive therapy, children with T-cell ALL have an outcome approaching that
of children with B-lineage ALL.[17,29,32,33,62]
There are few commonly accepted prognostic factors for patients with T-cell ALL. Conflicting data
exist regarding the prognostic significance of presenting leukocyte counts in T-cell ALL.[6,29-35]
The presence or absence of a mediastinal mass at diagnosis has no prognostic significance. In
patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance.
[76]
Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy) are rare in T-cell ALL.
[77,78]
Multiple chromosomal translocations have been identified in T-cell ALL, with many genes encoding
for transcription factors (e.g., TAL1, LMO1 and LMO2, LYL1, TLX1/HOX11, and TLX3/HOX11L2)
fusing to one of the T-cell receptor loci and resulting in aberrant expression of these transcription
factors in leukemia cells.[77,79-83] These translocations are often not apparent by examining a
standard karyotype, but are identified using more sensitive screening techniques, such as
fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR).[77] High expression
of TLX1/HOX11 resulting from translocations involving this gene occurs in 5% to 10% of pediatric
T-cell ALL cases and is associated with more favorable outcome in both adults and children with T-
cell ALL.[79-81,83] Overexpression of TLX3/HOX11L2 resulting from the cryptic t(5;14)(q35;q32)
translocation occurs in approximately 20% of pediatric T-cell ALL cases and appears to be
associated with increased risk of treatment failure,[81] although not in all studies.
Notch pathway signaling is commonly activated by NOTCH1 and FBXW7 gene mutations in T-cell
ALL.[84] NOTCH1-activating gene mutations occur in approximately 50% of T-cell ALL cases, and
FBXW7 inactivating gene mutations occur in approximately 15% of cases, with the result that
approximately 60% of cases having Notch pathway activation by mutations in at least one of these
genes. The prognostic significance of Notch pathway activation by NOTCH1 and FBXW7 mutations
in pediatric T-cell ALL is not clear, as some studies have shown a favorable prognosis for mutated
cases,[85-87] while other studies have not shown prognostic significance for the presence of
NOTCH1 and/or FBXW7 mutations.[88-90]
A NUP214ABL1 fusion has been noted in 4% to 6% of T-cell ALL cases and is observed in both
adults and children with a male predominance.[91-93] The fusion is cytogenetically cryptic and is
seen in FISH on amplified episomes or more rarely, as a small homogeneous staining region.[93] T-
cell ALL may also uncommonly show ABL1 fusion proteins with other gene partners (e.g., ETV6,
BCR, and EML1).[93] ABL tyrosine kinase inhibitors, such as imatinib or dasatinib, may have
therapeutic benefit in this T-cell ALL subtype,[91,92,94] although clinical experience with this
strategy is very limited.[95-97]
Early T-cell precursor ALL
Early T-cell precursor ALL, a distinct subset of childhood T-cell ALL, was initially defined by
identifying T-cell ALL cases with gene expression profiles highly related to expression profiles for
normal early T-cell precursors.[36] The subset of T-cell ALL cases, identified by these analyses
represented 13% of all cases and they were characterized by a distinctive immunophenotype (CD1a
and CD8 negativity, with weak expression of CD5 and coexpression of stem cell or myeloid
markers). Detailed molecular characterization of early T-cell precursor ALL showed this entity to
be highly heterogeneous at the molecular level, with no single gene affected by mutation or copy
number alteration in more than one-third of cases.[98] Compared with other T-ALL cases, the early
T-cell precursor group had a lower rate of NOTCH1 mutations and significantly higher frequencies
of alterations in genes regulating cytokine receptors and Ras signaling, hematopoietic
development, and histone modification. The transcriptional profile of early T-cell precursor ALL
shows similarities to that of normal hematopoietic stem cells and myeloid leukemia stem cells.[98]
Retrospective analyses have suggested that this subset has a poorer prognosis than other cases of
T-cell ALL.[36,99,100] However, further study in larger patient cohorts is needed.
Studies have found that the absence of biallelic deletion of the TCRgamma locus (ABGD), as
detected by comparative genomic hybridization and/or quantitative DNA-PCRn, was associated
with early treatment failure in patients with T-cell ALL.[101,102] ABGD is characteristic of early
thymic precursor cells, and many of the T-cell ALL patients with ABGD have an immunophenotype
consistent with the diagnosis of early T-cell precursor phenotype.
3. Myeloid antigen expression
Up to one-third of childhood ALL cases have leukemia cells that express myeloid-associated
surface antigens. Myeloid-associated antigen expression appears to be associated with specific ALL
subgroups, notably those with MLL translocations and those with the ETV6-RUNX1 gene
rearrangement.[103,104] No independent adverse prognostic significance exists for myeloid-
surface antigen expression.[103,104]
Leukemia of ambiguous lineage

Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of
both myeloid and lymphoid lineage.[105-107] These cases are distinct from ALL with myeloid
coexpression in that the predominant lineage cannot be determined by immunophenotypic and
histochemical studies. The definition of leukemia of ambiguous lineage varies among studies.
However, most investigators now use criteria established by the European Group for the
Immunological Characterization of Leukemias (EGIL) or the more stringent WHO criteria.[108-
110] In the WHO classification, the presence of myeloperoxidase is required to establish myeloid
lineage. This is not the case for the EGIL classification.
Leukemias of mixed phenotype comprise the following two groups:[105]
Bilineal leukemias in which there are two distinct populations of cells, usually one lymphoid
and one myeloid.
Biphenotypic leukemias in which individual blast cells display features of both lymphoid and
myeloid lineage. Biphenotypic cases represent the majority of mixed phenotype leukemias.
[105] Patients with B-myeloid biphenotypic leukemias lacking the ETV6-RUNX1 fusion have
a lower rate of complete remission and a significantly worse EFS than do patients with B-
precursor ALL. Some studies suggest that patients with biphenotypic leukemia may fare
better with a lymphoid, as opposed to a myeloid, treatment regimen,[106,107,111] although
the optimal treatment for patients remains unclear.
A number of recurrent chromosomal abnormalities have been shown to have prognostic significance,
especially in B-precursor ALL. Some chromosomal abnormalities are associated with more favorable
outcomes, such as high hyperdiploidy (5165 chromosomes) and the ETV6-RUNX1 fusion. Others are
associated with a poorer prognosis, including the Philadelphia chromosome (t(9;22)), rearrangements of
the MLL gene (chromosome 11q23), and intrachromosomal amplification of the AML1 gene (iAMP21).
[112]
Prognostically significant chromosomal abnormalities in childhood ALL include the following:
1. Chromosome number
High hyperdiploidy
High hyperdiploidy, defined as 51 to 65 chromosomes per cell or a DNA index greater than
1.16, occurs in 20% to 25% of cases of precursor B-cell ALL, but very rarely in cases of T-cell
ALL.[113] Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA
index) or by karyotyping. In cases with a normal karyotype or in which standard cytogenetic
analysis was unsuccessful, interphase FISH may detect hidden hyperdiploidy. High
hyperdiploidy generally occurs in cases with clinically favorable prognostic factors (patients
aged 1 to <10 years with a low WBC count) and is itself an independent favorable prognostic
factor.[19,113,114] Within the hyperdiploid range of 51 to 66 chromosomes, patients with
higher modal numbers (5866) appeared to have a better prognosis in one study.[19]
Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and

accumulate higher levels of methotrexate and its active polyglutamate metabolites,[115]
which may explain the favorable outcome commonly observed in these cases.
While the overall outcome of patients with high hyperdiploidy is considered to be favorable,
factors such as age, WBC count, specific trisomies, and early response to treatment have
been shown to modify its prognostic significance.[116]
Patients with trisomies of chromosomes 4, 10, and 17 (triple trisomies) have been shown to
have a particularly favorable outcome as demonstrated by both Pediatric Oncology Group
(POG) and Children's Cancer Group (CCG) analyses of NCI standard-risk ALL.[117] POG data
suggest that NCI standard-risk patients with trisomies of 4 and 10, without regard to
chromosome 17 status, have an excellent prognosis.[118]
Chromosomal translocations may be seen with high hyperdiploidy, and in those cases,
patients are more appropriately risk-classified based on the prognostic significance of the
translocation. For instance, in one study, 8% of patients with the Philadelphia chromosome
(t(9;22)) also had high hyperdiploidy,[119] and the outcome of these patients (treated
without tyrosine kinase inhibitors) was inferior to that observed in non-Philadelphia
chromosomepositive (Ph+) high hyperdiploid patients.
Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled
(masked hypodiploidy).[120] These cases may be interpretable based on the pattern of gains
and losses of specific chromosomes. These patients have an unfavorable outcome, similar to
those with hypodiploidy.[120]
Near triploidy (6880 chromosomes) and near tetraploidy (>80 chromosomes) are much
less common and appear to be biologically distinct from high hyperdiploidy.[121] Unlike
high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6-
RUNX1 fusion.[121-123] Near triploidy and tetraploidy were previously thought to be
associated with an unfavorable prognosis, but later studies suggest that this may not be the
case.[121,123]
Hypodiploidy (<44 chromosomes)
Precursor B-cell ALL cases with fewer than the normal number of chromosomes have been
subdivided in various ways, with one report stratifying based on modal chromosome number
into the following four groups:[120]
Near-haploid: 24 to 29 chromosomes (n = 46).

Low-hypodiploid: 33 to 39 chromosomes (n = 26).
High-hypodiploid: 40 to 43 chromosomes (n = 13).
Near-diploid: 44 chromosomes (n = 54).
Most patients with hypodiploidy are in the near-haploid and low-hypodiploid groups, and
both of these groups have an elevated risk of treatment failure compared with
nonhypodiploid cases.[120,124] Patients with fewer than 44 chromosomes have a worse

outcome than do patients with 44 or 45 chromosomes in their leukemic cells.[120]
The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be

distinctive from each other and from other types of ALL.[125] In near-haploid ALL,
alterations targeting receptor tyrosine kinase signaling, Ras signaling, and IKZF3 are
common. In low-hypodiploid ALL, genetic alterations involving TP53, RB1, and IKZF2 are
common. Importantly, the TP53 alterations observed in low-hypodiploid ALL are also
present in nontumor cells in approximately 40% of cases, suggesting that these mutations
are germline and that low-hypodiploid ALL represents, in some cases, a manifestation of Li-
Fraumeni syndrome.[125]
2. Chromosomal translocations
ETV6-RUNX1 (t(12;21) cryptic translocation, formerly known as TEL-AML1)
Fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 can be
detected in 20% to 25% of cases of B-precursor ALL but is rarely observed in T-cell ALL.
[122] The t(12;21) occurs most commonly in children aged 2 to 9 years.[126,127] Hispanic
children with ALL have a lower incidence of t(12;21) than do white children.[128]
Reports generally indicate favorable EFS and OS in children with the ETV6-RUNX1 fusion;
however, the prognostic impact of this genetic feature is modified by the following factors:
[129-132]
Early response to treatment.
NCI risk category (age and WBC count at diagnosis).
Treatment regimen.
In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of
prognostic factors found age and leukocyte count, but not ETV6-RUNX1, to be independent
prognostic factors.[129] There is a higher frequency of late relapses in patients with ETV6-
RUNX1 fusion compared with other B-precursor ALL.[129,133] Patients with the ETV6-
RUNX1 fusion who relapse seem to have a better outcome than other relapse patients,[134]
with an especially favorable prognosis for patients who relapse more than 36 months from
diagnosis.[135] Some relapses in patients with t(12;21) may represent a new independent
second hit in a persistent preleukemic clone (with the first hit being the ETV6-RUNX1
translocation).[136,137]
Philadelphia chromosome (t(9;22) translocation)
The Philadelphia chromosome t(9;22) is present in approximately 3% of children with ALL

and leads to production of a BCR-ABL1 fusion protein with tyrosine kinase activity (see
Figure 2).
Figure 2 . The Philadelphia chrom osom e is a translocation between the

ABL-1 oncogene (on the long arm of chrom osom e 9 ) and the breakpoint
cluster region (BCR) (on the long arm of chrom osom e 2 2 ), resulting in the
fusion gene BCR-ABL. BCR-ABL encodes an oncogenic protein with
ty rosine kinase activ ity .
This subtype of ALL is more common in older children with precursor B-cell ALL and high
WBC count.
Historically, the Philadelphia chromosome t(9;22) was associated with an extremely poor
prognosis (especially in those who presented with a high WBC count or had a slow early
response to initial therapy), and its presence had been considered an indication for allogeneic
hematopoietic stem cell transplantation (HSCT) in patients in first remission.[119,138-140]
Inhibitors of the BCR-ABL tyrosine kinase, such as imatinib mesylate, are effective in
patients with Ph+ ALL.[141] A study by the COG, which used intensive chemotherapy and
concurrent imatinib mesylate given daily, demonstrated a 3-year EFS rate of 80.5%, which
was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor
(imatinib mesylate) era.[141,142] Longer follow-up is necessary to determine whether this
treatment improves the cure rate or merely prolongs DFS.
MLL translocations
Translocations involving the MLL (11q23) gene occur in up to 5% of childhood ALL cases
and are generally associated with an increased risk of treatment failure.[71,143-145] The
t(4;11) translocation is the most common translocation involving the MLL gene in children
with ALL and occurs in approximately 2% of cases.[143]
Patients with the t(4;11) translocation are usually infants with high WBC counts; they are
more likely than other children with ALL to have CNS disease and to have a poor response to
initial therapy.[10] While both infants and adults with the t(4;11) translocation are at high
risk of treatment failure, children with the t(4;11) translocation appear to have a better
outcome than either infants or adults.[71,143] Irrespective of the type of MLL gene
rearrangement, infants with leukemia cells that have MLL gene rearrangements have a worse
treatment outcome than older patients whose leukemia cells have an MLL gene
rearrangement.[71,143] Deletion of the MLL gene has not been associated with an adverse
prognosis.[146]
Of interest, the t(11;19) translocation involving MLL and MLLT1/ENL occurs in

approximately 1% of ALL cases and occurs in both early B-lineage and T-cell ALL.[147]
Outcome for infants with the t(11;19) translocation is poor, but outcome appears relatively
favorable in older children with T-cell ALL and the t(11;19) translocation.[147]
TCF3-PBX1 (E2A-PBX1; t(1;19) translocation)
The t(1;19) translocation occurs in approximately 5% of childhood ALL cases and involves
fusion of the E2A gene on chromosome 19 to the PBX1 gene on chromosome 1.[73,74] The
t(1;19) translocation may occur as either a balanced translocation or as an unbalanced
translocation and is primarily associated with pre-B ALL immunophenotype (cytoplasmic Ig
positive). Black children are more likely than white children to have pre-B ALL with the
t(1;19).[148]
The t(1;19) translocation had been associated with inferior outcome in the context of
antimetabolite-based therapy,[149] but the adverse prognostic significance was largely
negated by more aggressive multiagent therapies.[74,150] However, in a trial conducted by
SJCRH on which all patients were treated without cranial radiation, patients with the t(1;19)
translocation had an overall outcome comparable to children lacking this translocation, with
a higher risk of CNS relapse and a lower rate of bone marrow relapse, suggesting that more
intensive CNS therapy may be needed for these patients.[44,151]
3. Other genomic alterations
Numerous new genetic lesions have been discovered by various array comparative hybridization
and next-generation sequencing methods. Appreciation of these submicroscopic genomic
abnormalities and mutations is redefining the subclassification of ALL:[152-158]
Intrachromosomal amplification of chromosome 21 (iAMP21): iAMP21 with

multiple extra copies of the RUNX1 (AML1) gene occurs in 1% to 2% of precursor B-cell ALL
cases and may be associated with an inferior outcome.[112,159,160]
IKZF1 deletions: IKZF1 deletions, including deletions of the entire gene and deletions of
specific exons, are present in approximately 15% of precursor B-cell ALL cases. Cases with
IKZF1 deletions tend to occur in older children, have a higher WBC count at diagnosis, and
are therefore, more common among NCI high-risk patients compared with NCI standard-risk
patients.[161,162] A high proportion of BCR-ABL1 cases have a deletion of IKZF1,[162,163]
and ALL arising in children with Down syndrome appears to have elevated rates of IKZF1
deletions.[58] IKZF1 deletions are also common in cases with CRLF2 genomic alterations and
in Philadelphia chromosomelike (Ph-like) ALL (see below).[152,162,164]
Multiple reports have documented the adverse prognostic significance of an IKZF1 deletion,
and most studies have reported that this deletion is an independent predictor of poor
outcome on multivariate analyses.[152,162,164-169]
CRLF2 and JAK mutations: Genomic alterations in CRLF2, a cytokine receptor gene
located on the pseudoautosomal regions of the sex chromosomes, have been identified in 5%
to 10% of cases of B-precursor ALL.[170,171] The chromosomal abnormalities that
commonly lead to CRLF2 overexpression include translocations of the IgH locus
(chromosome 14) to CRLF2 and interstitial deletions in pseudoautosomal regions of the sex
chromosomes, resulting in a P2RY8-CRLF2 fusion.[170-173] CRLF2 abnormalities are
strongly associated with the presence of IKZF1 deletions and JAK mutations;[54,162,171-
173] they are also more common in children with Down syndrome.[171] Point mutations in
kinase genes other than JAK1 and JAK2 are uncommon in CRLF2-overexpressing cases.[173]
Although the results of several retrospective studies suggest that CRLF2 abnormalities may
have adverse prognostic significance on univariate analyses, most do not find this
abnormality to be an independent predictor of outcome.[155,170-172,174] For example, in a
large European study, increased expression of CRLF2 was not associated with unfavorable
outcome in multivariate analysis, while IKZF1 deletion and BCR-ABL-like expression
signatures were associated with unfavorable outcome.[169] There is also controversy about
whether the prognostic significance of CRLF2 abnormalities should be analyzed based on
CRLF2 overexpression or on the presence of CRLF2 genomic alterations.[155,174]
Ph-like ALL: BCR-ABL1negative patients with a gene expression profile similar to BCR-
ABL1positive patients have been referred to as Ph-like ALL.[164,165] This occurs in 10% to
15% of pediatric ALL patients, increasing in frequency with age, and is associated with a poor
prognosis and with IKZF1 deletion/mutation.[157,164,165,169,173] The hallmark of this
entity is activated kinase signaling, with 50% containing CRLF2 genomic alterations [172]
and 25% concomitant JAK mutations.[54] Many of the remaining cases have been noted to
have a series of translocations with a common theme of involvement of either ABL1, JAK2,
PDGFRB, or EPOR.[157] Fusion proteins from these gene combinations have been noted in
some cases to be transformative and have responded to tyrosine kinase inhibitors both in
vitro and in vivo,[157] suggesting potential therapeutic strategies for these patients. Point
mutations in kinase genes, aside from those in JAK1 and JAK2, are uncommon in Ph-like ALL
cases.[173]
4. Gene polymorphisms in drug metabolic pathways
A number of polymorphisms of genes involved in the metabolism of chemotherapeutic agents have

been reported to have prognostic significance in childhood ALL.[175-177] For example, patients
with mutant phenotypes of thiopurine methyltransferase (a gene involved in the metabolism of
thiopurines, such as 6-mercaptopurine), appear to have more favorable outcomes,[178] although
such patients may also be at higher risk of developing significant treatment-related toxicities,
including myelosuppression and infection.[179,180]
Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms

associated with high end-induction minimal residual disease (MRD) and risk of relapse.
Polymorphisms of IL-15, as well as genes associated with the metabolism of etoposide and
methotrexate, were significantly associated with treatment response in two large cohorts of ALL
patients treated on SJCRH and COG protocols.[181] Polymorphic variants involving the reduced
folate carrier and methotrexate metabolism have been linked to toxicity and outcome.[182,183]
While these associations suggest that individual variations in drug metabolism can affect outcome,
few studies have attempted to adjust for these variations; whether individualized dose modification
based on these findings will improve outcome is unknown.
Response to initial treatment affecting prognosis
The rapidity with which leukemia cells are eliminated after initiation of treatment and the level of residual
disease at the end of induction are associated with long-term outcome. Because treatment response is
influenced by the drug sensitivity of leukemic cells and host pharmacodynamics and pharmacogenomics,
[184] early response has strong prognostic significance. Various ways of evaluating the leukemia cell
response to treatment have been utilized, including the following:
1. MRD determination.
2. Day 7 and day 14 bone marrow responses.
3. Peripheral blood response to steroid prophase.
4. Peripheral blood response to multiagent induction therapy.
5. Peripheral blood MRD before end of induction (day 8, day 15).
6. Induction failure.
MRD determination
Morphologic assessment of residual leukemia in blood or bone marrow is often difficult and is relatively
insensitive. Traditionally, a cutoff of 5% blasts in the bone marrow (detected by light microscopy) has
been used to determine remission status. This corresponds to a level of 1 in 20 malignant cells. If one
wishes to detect lower levels of leukemic cells in either blood or marrow, specialized techniques such as
PCR assays, which determine unique Ig/T-cell receptor gene rearrangements, fusion transcripts produced
by chromosome translocations, or flow cytometric assays, which detect leukemia-specific
immunophenotypes, are required. With these techniques, detection of as few as 1 leukemia cell in
100,000 normal cells is possible, and MRD at the level of 1 in 10,000 cells can be detected routinely.
[185]
Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of
outcome in children and adolescents with B-lineage ALL.[130,186-189] MRD response discriminates
outcome in subsets of patients defined by age, leukocyte count, and cytogenetic abnormalities.[190]
Patients with higher levels of end-induction MRD have a poorer prognosis than those with lower or
undetectable levels.[130,185-187,191] End-induction MRD is used by almost all groups as a factor
determining the intensity of postinduction treatment, with patients found to have higher levels allocated
to more intensive therapies. MRD levels at earlier (e.g., day 8 and day 15 of induction) and later time
points (e.g., week 12 of therapy) also predict outcome.[130,185,187,190-195]
MRD measurements, in conjunction with other presenting features, have also been used to identify
subsets of patients with an extremely low risk of relapse. The COG reported a very favorable prognosis (5-
year EFS of 97% 1%) for patients with B-precursor phenotype, NCI standard risk age/leukocyte count,
CNS1 status, and favorable cytogenetic abnormalities (either high hyperdiploidy with favorable trisomies
or the ETV6-RUNX1 fusion) who had less than 0.01% MRD levels at both day 8 (from peripheral blood)
and end-induction (from bone marrow).[130]
There are fewer studies documenting the prognostic significance of MRD in T-cell ALL. In the AIEOP-
BFM ALL 2000 trial, MRD status at day 78 (week 12) was the most important predictor for relapse in
patients with T-cell ALL. Patients with detectable MRD at end-induction who had negative MRD by day 78
did just as well as patients who achieved MRD-negativity at the earlier end-induction time point. Thus,
unlike in B-cell precursor ALL, end-induction MRD levels were irrelevant in those patients whose MRD
was negative at day 78. A high MRD level at day 78 was associated with a significantly higher risk of
relapse.[195]
There are few studies of MRD in the CSF. In one study, MRD was documented in about one-half of
children at diagnosis.[196] In this study, CSF MRD was not found to be prognostic when intensive
chemotherapy was given.
Although MRD is the most important prognostic factor in determining outcome, there are no data to
conclusively show that modifying therapy based on MRD determination significantly improves outcome
in newly diagnosed ALL.[190] However, the UKALL 2003 study demonstrated that reduction of therapy
(i.e., one rather than two courses of delayed intensification) did not adversely impact outcome in non-
highrisk patients with favorable end-induction MRD.[197][Level of evidence: 1iiDii]
Day 7 and day 14 bone marrow responses
Patients who have a rapid reduction in leukemia cells to less than 5% in their bone marrow within 7 or 14
days after the initiation of multiagent chemotherapy have a more favorable prognosis than do patients
who have slower clearance of leukemia cells from the bone marrow.[198] MRD assessments at the end of
induction therapy have generally replaced day 7 and day 14 morphological assessments as response to
therapy prognostic indicators because the latter lose their prognostic significance in multivariate analysis
once MRD is included in the analyses.[130,199]
Peripheral blood response to steroid prophase
Patients with a reduction in peripheral blast count to less than 1,000/L after a 7-day induction prophase
with prednisone and one dose of intrathecal methotrexate (a good prednisone response) have a more
favorable prognosis than do patients whose peripheral blast counts remain above 1,000/L (a poor
prednisone response).[17] Poor prednisone response is observed in fewer than 10% of patients.[17,200]
Treatment stratification for protocols of the Berlin-Frankfurt-Mnster (BFM) clinical trials group is
partially based on early response to the 7-day prednisone prophase (administered immediately before the
initiation of multiagent remission induction).
Peripheral blood response to multiagent induction therapy
Patients with persistent circulating leukemia cells at 7 to 10 days after the initiation of multiagent
chemotherapy are at increased risk of relapse compared with patients who have clearance of peripheral
blasts within 1 week of therapy initiation.[201] Rate of clearance of peripheral blasts has been found to be
of prognostic significance in both T-cell and B-lineage ALL.[201]
Peripheral blood MRD before end of induction (day 8, day 15)
MRD using peripheral blood obtained 1 week after the initiation of multiagent induction chemotherapy
has also been evaluated as an early response-to-therapy prognostic factor. In a COG study involving
nearly 2,000 children with ALL, the presence of MRD in the peripheral blood at day 8 was associated with
adverse prognosis, with increasing MRD levels being associated with a progressively poorer outcome.
[130] In multivariate analysis, end of induction therapy MRD was the most powerful prognostic factor,
but day 8 peripheral blood MRD maintained its prognostic significance, as did NCI risk group and the
presence of favorable trisomies. A smaller study assessed the prognostic significance of peripheral blood
MRD at day 15 after 1 week of a steroid prophase and 1 week of multiagent induction therapy.[202] This
study also observed multivariate significance for peripheral blood MRD levels after 1 week of multiagent
induction therapy. Both studies identified a group of patients who achieved low MRD levels after 1 week
of multiagent induction therapy who had a low rate of subsequent treatment failure.
Induction failure
The vast majority of children with ALL achieve complete morphologic remission by the end of the first
month of treatment. The presence of greater than 5% lymphoblasts at the end of the induction phase is
observed in up to 5% of children with ALL.[203] Patients at highest risk of induction failure have one or
more of the following features:[204,205]
T-cell phenotype (especially without a mediastinal mass).
B-precursor ALL with very high presenting leukocyte counts.
11q23 rearrangement.
Older age.
Philadelphia chromosome.
In a large retrospective study, the OS of patients with induction failure was only 32%.[203] However,
there was significant clinical and biological heterogeneity. A relatively favorable outcome was observed in
patients with B-precursor ALL between the ages of 1 and 5 years without adverse cytogenetics (MLL
translocation or BCR-ABL). This group had a 10-year survival exceeding 50%, and HSCT in first
remission was not associated with a survival advantage compared with chemotherapy alone for this
subset. Patients with the poorest outcomes (<20% 10-year survival) included those who were aged 14 to
18 years, or who had the Philadelphia chromosome or MLL rearrangement. B-cell ALL patients younger
than 6 years and T-cell ALL patients (regardless of age) appeared to have better outcomes if treated with
allogeneic HSCT after achieving complete remission than those who received further treatment with
chemotherapy alone.
Prognostic (Risk) Groups
For decades, clinical trial groups studying childhood ALL have utilized risk classification schemes to
assign patients to therapeutic regimens based on their estimated risk of treatment failure. Initial risk
classification systems utilized clinical factors such as age and presenting WBC count. Response to therapy
measures were subsequently added, with some groups utilizing early morphologic bone marrow response
(e.g., at day 8 or day 15) and with other groups utilizing response of circulating leukemia cells to single
agent prednisone. Modern risk classification systems continue to utilize clinical factors such as age and
presenting WBC count, and in addition, incorporate molecular characteristics of leukemia cells at
diagnosis (e.g., favorable and unfavorable translocations) and response to therapy based on detection of
MRD at end of induction (and in some cases at later time points). The risk classification systems of the
COG and the BFM groups are briefly described below.
Childrens Oncology Group (COG) risk groups
In COG protocols, children with ALL are initially stratified into treatment groups (with varying degrees of
risk of treatment failure) based on a subset of prognostic factors, including the following:
Age.
WBC count at diagnosis.
Immunophenotype.
Cytogenetics/genomic alterations.
Presence of extramedullary disease.
Down syndrome.
Steroid pretreatment.
EFS rates exceed 85% in children meeting good-risk criteria (aged 1 to <10 years, WBC count <50,000/
L, and precursor B-cell immunophenotype); in children meeting high-risk criteria, EFS rates are
approximately 75%.[3,44,200,206,207] Additional factors, including cytogenetic abnormalities and
measures of early response to therapy (e.g., day 7 and/or day 14 marrow blast percentage for patients
with Down syndrome and MRD levels in peripheral blood on day 8 and in bone marrow samples at the end
of induction), considered in conjunction with presenting age, WBC count, immunophenotype, the
presence of extramedullary disease, and steroid pretreatment can identify patient groups for
postinduction therapy with expected EFS rates ranging from less than 40% to more than 95%.[3,130]
Patients who are at very high risk of treatment failure include the following: [9,208-210]
Infants with MLL translocations.
Patients with hypodiploidy (<44 chromosomes).
Patients with initial induction failure.
Berlin-Frankfurt-Mnster (BFM) risk groups
Since 2000, risk stratification on BFM protocols has been based almost solely on treatment response
criteria. In addition to prednisone prophase response, treatment response is assessed via MRD
measurements at two time points, end induction (week 5) and end consolidation (week 12).
The BFM risk groups include the following:[190]
Standard risk: Patients who are MRD-negative (i.e., <10-4 ) at both time points are classified as
standard risk.
Intermediate risk: Patients who have positive MRD at week 5 and low MRD (<10-3 ) at week 12 are
considered intermediate risk.
High risk: Patients with high MRD (10-3 ) at week 12 are high risk. Patients with a poor response to
the prednisone prophase are also considered high risk, regardless of subsequent MRD.
Phenotype, leukemic cell mass estimate, also known as BFM risk factor, and CNS status at diagnosis do
not factor into the current risk classification schema. However, patients with either the t(9;22) or the
t(4;11) are considered high risk, regardless of early response measures.
Prognostic (risk) groups under clinical evaluation
COG AALL08B1 (Classification of Newly Diagnosed ALL): COG protocol AALL08B1 stratifies four risk
groups for patients with B-precursor ALL (low risk, average risk, high risk, and very high risk) based on
the following criteria:
Age and presenting leukocyte count (using NCI risk-group criteria).[1]
Extramedullary disease (presence or absence of CNS and/or testicular leukemia).
Genomic alterations in leukemia cells.
Day 8 peripheral blood MRD.
Day 29 bone marrow morphologic response and MRD.
Down syndrome.
Steroid pretreatment.
Morphologic assessment of early response in the bone marrow is no longer performed on days 8 and 15 of
induction as part of risk stratification. Patients with T-cell phenotype are treated on a separate study and
are not risk classified in this way.
For patients with B-precursor ALL:
Favorable genetics are defined as the presence of either hyperdiploidy with trisomies of
chromosomes 4 and 10 (double trisomy) or the ETV6-RUNX1 fusion.
Unfavorable characteristics are defined as CNS3 status at diagnosis, induction failure (M3 marrow
at day 29), age 13 years and older, and the following unfavorable genomic alterations: hypodiploidy
(<44 chromosomes or DNA index <0.81), MLL rearrangement, and iAMP21. The presence of any
of these unfavorable characteristics is sufficient to classify a patient as very high risk, regardless of
other presenting features. Infants and children with BCR-ABL (Ph+ ALL) are treated on a separate
clinical trial.
MRD levels at day 8 from peripheral blood and at day 29 from bone marrow are used in risk
classification.
The four risk groups for B-precursor ALL are defined in Table 1.
Table 1. Risk Groups for B-Precursor Acute Lymphoblastic Leukemiaa

Enlarge
Low A v er a ge Ri sk Hi gh Ri sk V er y Hi gh Ri sk
Ri sk
NCI Ri sk SR SR SR SR SR HR SR HR HR SR or
(A ge/WBC) (a g e (a g e HR
<1 3 y ) 1 3 y )
Fa v or a bl e Y es Y es No Y es No Any No Any Any Any

Gen et i cs
Un fa v or a bl e Non e Non e Non e Non e Non e Non e Non e Non e Non e Y es

Ch a r a ct er i st i cs
Da y 8 PB MRD <0 .0 1 % 0 .0 1 % <1 % Any 1 % Any Any Any Any Any

Lev el Lev el Lev el Lev el Lev el Lev el
Da y 29 Ma r r ow <0 .0 1 % <0 .0 1 % <0 .0 1 % 0 .0 1 % <0 .0 1 % <0 .0 1 % 0 .0 1 % 0 .0 1 % <0 .0 1 % Any

MRD Lev el
% of Pa t i en t s 15% 36% 25% 24%

(Est i m a t ed)
A n t i ci pa t ed 5- >9 5 % 9 0 %9 5 % 8 8 %9 0 % <8 0 %
y ea r EFS
EFS = event-free s urvival; HR = age and WBC count ris k group is high ris k ; MRD = m inim al res idual dis eas e; NCI =
National Cancer Ins titute; PB = peripheral blood; SR = age/WBC count ris k group is s tandard ris k ; WBC = w hite blood
cell.
a From the Children's Oncology Group Clas s ification of New ly Diagnos ed ALL protocol.
AALL0434 (NCT 00408005) (Combination Chemotherapy in Treating Young Patients With Newly
Diagnosed T-Cell Acute Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma): For patients with
T-cell ALL, COG uses the following criteria to assign risk category:
Low risk
NCI standard risk by age (1.009.99 years) and WBC count (initial 50,000/L).
M1 marrow on day 15 and M1 marrow with MRD <0.1% on day 29.
CNS1 status and no testicular disease at diagnosis.
Intermediate risk
Doesnt meet criteria for low risk.

M1 marrow with MRD <1% on day 29.
Any CNS status.
High risk
M2 marrow and/or MRD 1% on day 29.

Any CNS status.
DFCI-11-001 (NCT 01574274) (SC-PEG Asparaginase vs. Oncaspar in Pediatric ALL and
Lymphoblastic Lymphoma): On the current clinical trial conducted by the Dana-Farber Cancer Institute
ALL Consortium, patients with B-precursor ALL are initially classified as either standard risk or high risk
based on age, presenting leukocyte count, and the presence or absence of CNS disease (CNS3). At the
completion of a five-drug remission induction regimen (4 weeks from diagnosis), the level of MRD is
determined via PCR assay. Patients with high MRD (0.001) are classified as very high risk and receive a
more intensive postremission consolidation. Patients with low MRD (<0.001) continue to receive
treatment based on their initial risk group classification. The goal of this new classification schema is to
determine whether intensification of therapy will improve the outcome of patients with high MRD at the
end of remission induction. Patients with T-cell ALL are treated as high risk, regardless of MRD status. All
patients with MLL translocations or hypodiploidy (<44 chromosomes) are classified as very high risk,
regardless of MRD status or phenotype. Ph+ patients are removed from study midinduction and are
eligible to enroll on the COG protocol for patients with Ph+ ALL.
SJCRH (T otal XVI): Patients are classified into one of three categories (low, standard, or high risk)
based on the presenting age, leukocyte count, presence or absence of CNS3 status or testicular leukemia,
immunophenotype, cytogenetics and molecular genetics, DNA index, and early response to therapy.
Hence, definitive risk assignment (for provisional low-risk or standard-risk cases based on presenting
features) will be made after completion of remission induction therapy. The criteria and the estimated
proportion of patients in each category (based on data from TOTXV study) are provided below.
Criteria for low-risk ALL (approximately 48% of patients)
B-cell precursor ALL with DNA index 1.16, ETV6-RUNX1 fusion, or age 1 to 9.9 years and
presenting WBC <50 109 /L.
Must not have:
CNS3 status (5 WBC/l of CSF with morphologically identifiable blasts or cranial nerve
palsy).
Overt testicular leukemia (evidenced by ultrasonogram).
Adverse genetic featurest(9;22) or BCR-ABL1 fusion; t(1;19) with E2A-PBX1 fusion;

rearranged MLL (as measured by FISH and/or PCR); or hypodiploidy (<44 chromosomes).
Poor early response (1% lymphoblasts on day 15 of remission induction, 0.01%

lymphoblasts by immunologic or molecular methods on remission date).
Criteria for standard-risk ALL (approximately 44% of patients)
All cases of T-cell ALL and those of B-cell precursor ALL that do not meet the criteria for low-risk
or high-risk ALL.
Criteria for high-risk ALL (approximately 8% of patients)
t(9;22) or BCR-ABL fusion.
Infants with t(4;11) or MLL fusion.
Induction failure or >1% leukemia lymphoblasts in the bone marrow on remission date.
>0.1% leukemic lymphoblasts in the bone marrow in week 7 of continuation treatment (i.e., before
reinduction 1, about 14 weeks postremission induction).
Re-emergence of leukemic lymphoblasts by MRD (at any level) in patients previously MRD
negative.
Persistently detectable MRD at lower levels.
Early T-cell precursor ALL, defined by low expression of T-cell markers together with aberrant
expression of myeloid markers.[36] The following features characterize early T-cell precursor
ALL:
Levels of CD5 expression at least tenfold lower than that of normal peripheral blood T-
lymphocytes. In the study that identified this subset of T-cell ALL, CD5 expression was
tenfold to more than 200-fold lower than that of normal lymphocytes and median
percentage of leukemic cells expressing CD5 in the 17 atypical cases was 45%; in contrast to
more than 98% for the 122 cases in the typical group.
Absence (<10%) of CD1a and CD8 expression.
Expression of cytoplasmic CD3 together with the expression of one or more markers
associated with myeloid leukemia such as HLA-Dr, CD34, CD13, CD33, or CD11b, while
myeloperoxidase is less than 3% by cytochemistry and/or flow cytometry.
childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location,
drug, intervention, and other criteria.
References
1. Smith M, Arthur D, Camitta B, et al.: Uniform approach to risk classification and treatment
assignment for children with acute lymphoblastic leukemia. J Clin Oncol 14 (1): 18-24, 1996.
[PUBMED A bstract]
2. Carroll WL, Bhojwani D, Min DJ, et al.: Pediatric acute lymphoblastic leukemia. Hematology (Am
Soc Hematol Educ Program) : 102-31, 2003. [PUBMED A bstract]
3. Schultz KR, Pullen DJ, Sather HN, et al.: Risk- and response-based classification of childhood B-
precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the
Pediatric Oncology Group (POG) and Children's Cancer Group (CCG). Blood 109 (3): 926-35,
4. Vrooman LM, Silverman LB: Childhood acute lymphoblastic leukemia: update on prognostic
factors. Curr Opin Pediatr 21 (1): 1-8, 2009. [PUBMED A bstract]
5. Pui CH, Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med 354 (2): 166-78,
6. Pullen J, Shuster JJ, Link M, et al.: Significance of commonly used prognostic factors differs for
children with T cell acute lymphocytic leukemia (ALL), as compared to those with B-precursor
ALL. A Pediatric Oncology Group (POG) study. Leukemia 13 (11): 1696-707, 1999. [PUBMED A bstract]
7. Mricke A, Zimmermann M, Reiter A, et al.: Prognostic impact of age in children and adolescents
with acute lymphoblastic leukemia: data from the trials ALL-BFM 86, 90, and 95. Klin Padiatr 217
(6): 310-20, 2005 Nov-Dec. [PUBMED A bstract]
8. Reaman GH, Sposto R, Sensel MG, et al.: Treatment outcome and prognostic factors for infants
with acute lymphoblastic leukemia treated on two consecutive trials of the Children's Cancer
Group. J Clin Oncol 17 (2): 445-55, 1999. [PUBMED A bstract]
9. Kosaka Y, Koh K, Kinukawa N, et al.: Infant acute lymphoblastic leukemia with MLL gene
rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell
transplantation. Blood 104 (12): 3527-34, 2004. [PUBMED A bstract]
10. Pieters R, Schrappe M, De Lorenzo P, et al.: A treatment protocol for infants younger than 1 year
with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre
randomised trial. Lancet 370 (9583): 240-50, 2007. [PUBMED A bstract]
11. Hilden JM, Dinndorf PA, Meerbaum SO, et al.: Analysis of prognostic factors of acute
lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood
108 (2): 441-51, 2006. [PUBMED A bstract]
12. Isoyama K, Eguchi M, Hibi S, et al.: Risk-directed treatment of infant acute lymphoblastic
leukaemia based on early assessment of MLL gene status: results of the Japan Infant Leukaemia
Study (MLL96). Br J Haematol 118 (4): 999-1010, 2002. [PUBMED A bstract]
13. Nagayama J, Tomizawa D, Koh K, et al.: Infants with acute lymphoblastic leukemia and a germline
MLL gene are highly curable with use of chemotherapy alone: results from the Japan Infant
Leukemia Study Group. Blood 107 (12): 4663-5, 2006. [PUBMED A bstract]
14. Sam TN, Kersey JH, Linabery AM, et al.: MLL gene rearrangements in infant leukemia vary with
age at diagnosis and selected demographic factors: a Children's Oncology Group (COG) study.
Pediatr Blood Cancer 58 (6): 836-9, 2012. [PUBMED A bstract]
15. Kang H, Wilson CS, Harvey RC, et al.: Gene expression profiles predictive of outcome and age in
infant acute lymphoblastic leukemia: a Children's Oncology Group study. Blood 119 (8): 1872-81,
16. Stam RW, Schneider P, de Lorenzo P, et al.: Prognostic significance of high-level FLT3 expression
in MLL-rearranged infant acute lymphoblastic leukemia. Blood 110 (7): 2774-5, 2007. [PUBMED
A bstract]
17. Schrappe M, Reiter A, Ludwig WD, et al.: Improved outcome in childhood acute lymphoblastic
leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM
90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95 (11): 3310-22, 2000. [PUBMED
A bstract]
18. Forestier E, Schmiegelow K; on behalf of the Nordic Society of Paediatric Haematology and
Oncology NOPHO.: The incidence peaks of the childhood acute leukemias reflect specific
cytogenetic aberrations. J Pediatr Hematol Oncol 28 (8): 486-95, 2006. [PUBMED A bstract]
19. Dastugue N, Suciu S, Plat G, et al.: Hyperdiploidy with 58-66 chromosomes in childhood B-acute
lymphoblastic leukemia is highly curable: 58951 CLG-EORTC results. Blood 121 (13): 2415-23,
20. Nachman JB, La MK, Hunger SP, et al.: Young adults with acute lymphoblastic leukemia have an
excellent outcome with chemotherapy alone and benefit from intensive postinduction treatment: a
report from the children's oncology group. J Clin Oncol 27 (31): 5189-94, 2009. [PUBMED A bstract]
21. Pulte D, Gondos A, Brenner H: Improvement in survival in younger patients with acute
lymphoblastic leukemia from the 1980s to the early 21st century. Blood 113 (7): 1408-11, 2009.
[PUBMED A bstract]
22. Pui CH, Pei D, Campana D, et al.: Improved prognosis for older adolescents with acute
lymphoblastic leukemia. J Clin Oncol 29 (4): 386-91, 2011. [PUBMED A bstract]
23. Childhood cancer. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics
Review, 1975-2010. Bethesda, Md: National Cancer Institute, based on November 2012 SEER data
submission, posted to the SEER web site, April 2013, Section 28. Also available online. Last
accessed April 04, 2014.
24. Childhood cancer by the ICCC. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer
Statistics Review, 1975-2010. Bethesda, Md: National Cancer Institute, based on November 2012
SEER data submission, posted to the SEER web site, April 2013, Section 29. Also available online.
Last accessed April 04, 2014.
25. Smith MA, Ries LA, Gurney JG, et al.: Leukemia. In: Ries LA, Smith MA, Gurney JG, et al., eds.:
Cancer incidence and survival among children and adolescents: United States SEER Program 1975-
1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp
17-34. Also available online. Last accessed April 04, 2014.
26. de Bont JM, Holt B, Dekker AW, et al.: Significant difference in outcome for adolescents with acute
lymphoblastic leukemia treated on pediatric vs adult protocols in the Netherlands. Leukemia 18
(12): 2032-5, 2004. [PUBMED A bstract]
27. Boissel N, Auclerc MF, Lhritier V, et al.: Should adolescents with acute lymphoblastic leukemia be
treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials.
J Clin Oncol 21 (5): 774-80, 2003. [PUBMED A bstract]
28. Stock W, La M, Sanford B, et al.: What determines the outcomes for adolescents and young adults
with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of
Children's Cancer Group and Cancer and Leukemia Group B studies. Blood 112 (5): 1646-54, 2008.
[PUBMED A bstract]
29. Goldberg JM, Silverman LB, Levy DE, et al.: Childhood T-cell acute lymphoblastic leukemia: the
Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol
21 (19): 3616-22, 2003. [PUBMED A bstract]
30. Silverman LB, Stevenson KE, O'Brien JE, et al.: Long-term results of Dana-Farber Cancer Institute
ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-
2000). Leukemia 24 (2): 320-34, 2010. [PUBMED A bstract]
31. Pui CH, Pei D, Sandlund JT, et al.: Long-term results of St Jude Total Therapy Studies 11, 12, 13A,
13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia 24 (2): 371-82, 2010. [PUBMED
A bstract]
33. Mricke A, Zimmermann M, Reiter A, et al.: Long-term results of five consecutive trials in
childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to
2000. Leukemia 24 (2): 265-84, 2010. [PUBMED A bstract]
34. Slack JL, Arthur DC, Lawrence D, et al.: Secondary cytogenetic changes in acute promyelocytic
leukemia--prognostic importance in patients treated with chemotherapy alone and association with
the intron 3 breakpoint of the PML gene: a Cancer and Leukemia Group B study. J Clin Oncol 15 (5):
35. Vaitkeviien G, Forestier E, Hellebostad M, et al.: High white blood cell count at diagnosis of
childhood acute lymphoblastic leukaemia: biological background and prognostic impact. Results
from the NOPHO ALL-92 and ALL-2000 studies. Eur J Haematol 86 (1): 38-46, 2011. [PUBMED
A bstract]
36. Coustan-Smith E, Mullighan CG, Onciu M, et al.: Early T-cell precursor leukaemia: a subtype of
very high-risk acute lymphoblastic leukaemia. Lancet Oncol 10 (2): 147-56, 2009. [PUBMED A bstract]
37. Brger B, Zimmermann M, Mann G, et al.: Diagnostic cerebrospinal fluid examination in children
with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic
lumbar puncture. J Clin Oncol 21 (2): 184-8, 2003. [PUBMED A bstract]
38. Matloub Y, Bostrom BC, Hunger SP, et al.: Escalating intravenous methotrexate improves event-
free survival in children with standard-risk acute lymphoblastic leukemia: a report from the
Children's Oncology Group. Blood 118 (2): 243-51, 2011. [PUBMED A bstract]
39. Mahmoud HH, Rivera GK, Hancock ML, et al.: Low leukocyte counts with blast cells in
cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med
329 (5): 314-9, 1993. [PUBMED A bstract]
40. Sirvent N, Suciu S, Rialland X, et al.: Prognostic significance of the initial cerebro-spinal fluid (CSF)
involvement of children with acute lymphoblastic leukaemia (ALL) treated without cranial
irradiation: results of European Organization for Research and Treatment of Cancer (EORTC)
Children Leukemia Group study 58881. Eur J Cancer 47 (2): 239-47, 2011. [PUBMED A bstract]
41. te Loo DM, Kamps WA, van der Does-van den Berg A, et al.: Prognostic significance of blasts in the
cerebrospinal fluid without pleiocytosis or a traumatic lumbar puncture in children with acute
lymphoblastic leukemia: experience of the Dutch Childhood Oncology Group. J Clin Oncol 24 (15):
42. Gilchrist GS, Tubergen DG, Sather HN, et al.: Low numbers of CSF blasts at diagnosis do not predict
for the development of CNS leukemia in children with intermediate-risk acute lymphoblastic
leukemia: a Childrens Cancer Group report. J Clin Oncol 12 (12): 2594-600, 1994. [PUBMED A bstract]
43. Gajjar A, Harrison PL, Sandlund JT, et al.: Traumatic lumbar puncture at diagnosis adversely
affects outcome in childhood acute lymphoblastic leukemia. Blood 96 (10): 3381-4, 2000. [PUBMED
A bstract]
45. Tubergen DG, Cullen JW, Boyett JM, et al.: Blasts in CSF with a normal cell count do not justify
alteration of therapy for acute lymphoblastic leukemia in remission: a Childrens Cancer Group
study. J Clin Oncol 12 (2): 273-8, 1994. [PUBMED A bstract]
46. Cherlow JM, Sather H, Steinherz P, et al.: Craniospinal irradiation for acute lymphoblastic
leukemia with central nervous system disease at diagnosis: a report from the Children's Cancer
Group. Int J Radiat Oncol Biol Phys 36 (1): 19-27, 1996. [PUBMED A bstract]
47. Hijiya N, Liu W, Sandlund JT, et al.: Overt testicular disease at diagnosis of childhood acute
lymphoblastic leukemia: lack of therapeutic role of local irradiation. Leukemia 19 (8): 1399-403,
48. Sirvent N, Suciu S, Bertrand Y, et al.: Overt testicular disease (OTD) at diagnosis is not associated
with a poor prognosis in childhood acute lymphoblastic leukemia: results of the EORTC CLG Study
58881. Pediatr Blood Cancer 49 (3): 344-8, 2007. [PUBMED A bstract]
49. Bassal M, La MK, Whitlock JA, et al.: Lymphoblast biology and outcome among children with Down
syndrome and ALL treated on CCG-1952. Pediatr Blood Cancer 44 (1): 21-8, 2005. [PUBMED A bstract]
50. Zeller B, Gustafsson G, Forestier E, et al.: Acute leukaemia in children with Down syndrome: a
population-based Nordic study. Br J Haematol 128 (6): 797-804, 2005. [PUBMED A bstract]
51. Whitlock JA, Sather HN, Gaynon P, et al.: Clinical characteristics and outcome of children with
Down syndrome and acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 106
(13): 4043-9, 2005. [PUBMED A bstract]
52. Arico M, Ziino O, Valsecchi MG, et al.: Acute lymphoblastic leukemia and Down syndrome:
presenting features and treatment outcome in the experience of the Italian Association of Pediatric
Hematology and Oncology (AIEOP). Cancer 113 (3): 515-21, 2008. [PUBMED A bstract]
53. Maloney KW, Carroll WL, Carroll AJ, et al.: Down syndrome childhood acute lymphoblastic
leukemia has a unique spectrum of sentinel cytogenetic lesions that influences treatment outcome:
a report from the Children's Oncology Group. Blood 116 (7): 1045-50, 2010. [PUBMED A bstract]
54. Mullighan CG, Collins-Underwood JR, Phillips LA, et al.: Rearrangement of CRLF2 in B-progenitor-
and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet 41 (11): 1243-6, 2009.
[PUBMED A bstract]
55. Bercovich D, Ganmore I, Scott LM, et al.: Mutations of JAK2 in acute lymphoblastic leukaemias
associated with Down's syndrome. Lancet 372 (9648): 1484-92, 2008. [PUBMED A bstract]
56. Gaikwad A, Rye CL, Devidas M, et al.: Prevalence and clinical correlates of JAK2 mutations in
Down syndrome acute lymphoblastic leukaemia. Br J Haematol 144 (6): 930-2, 2009. [PUBMED
A bstract]
57. Kearney L, Gonzalez De Castro D, Yeung J, et al.: Specific JAK2 mutation (JAK2R683) and multiple
gene deletions in Down syndrome acute lymphoblastic leukemia. Blood 113 (3): 646-8, 2009.
[PUBMED A bstract]
58. Buitenkamp TD, Pieters R, Gallimore NE, et al.: Outcome in children with Down's syndrome and
acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations. Leukemia 26 (10):
59. Pui CH, Boyett JM, Relling MV, et al.: Sex differences in prognosis for children with acute
60. Shuster JJ, Wacker P, Pullen J, et al.: Prognostic significance of sex in childhood B-precursor acute
lymphoblastic leukemia: a Pediatric Oncology Group Study. J Clin Oncol 16 (8): 2854-63, 1998.
[PUBMED A bstract]
61. Chessells JM, Richards SM, Bailey CC, et al.: Gender and treatment outcome in childhood
lymphoblastic leukaemia: report from the MRC UKALL trials. Br J Haematol 89 (2): 364-72, 1995.
[PUBMED A bstract]
62. Silverman LB, Gelber RD, Dalton VK, et al.: Improved outcome for children with acute
lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 97 (5): 1211-8,
64. Bhatia S: Influence of race and socioeconomic status on outcome of children treated for childhood
acute lymphoblastic leukemia. Curr Opin Pediatr 16 (1): 9-14, 2004. [PUBMED A bstract]
65. Kadan-Lottick NS, Ness KK, Bhatia S, et al.: Survival variability by race and ethnicity in childhood
acute lymphoblastic leukemia. JAMA 290 (15): 2008-14, 2003. [PUBMED A bstract]
66. Bhatia S, Landier W, Shangguan M, et al.: Nonadherence to oral mercaptopurine and risk of relapse
in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the
children's oncology group. J Clin Oncol 30 (17): 2094-101, 2012. [PUBMED A bstract]
67. Yang JJ, Cheng C, Devidas M, et al.: Ancestry and pharmacogenomics of relapse in acute
68. Xu H, Cheng C, Devidas M, et al.: ARID5B genetic polymorphisms contribute to racial disparities in
the incidence and treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol 30
(7): 751-7, 2012. [PUBMED A bstract]
69. Bennett JM, Catovsky D, Daniel MT, et al.: The morphological classification of acute lymphoblastic
leukaemia: concordance among observers and clinical correlations. Br J Haematol 47 (4): 553-61,
70. Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic
and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008.
71. Pui CH, Chessells JM, Camitta B, et al.: Clinical heterogeneity in childhood acute lymphoblastic
leukemia with 11q23 rearrangements. Leukemia 17 (4): 700-6, 2003. [PUBMED A bstract]
72. Mricke A, Ratei R, Ludwig WD, et al.: Prognostic factors in CD10 negative precursor b-cell acute
lymphoblastic leukemia in children: data from three consecutive trials ALL-BFM 86, 90, and 95.
[Abstract] Blood 104 (11): A-1957, 540a, 2004.
73. Hunger SP: Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia:
clinical features and molecular pathogenesis. Blood 87 (4): 1211-24, 1996. [PUBMED A bstract]
74. Uckun FM, Sensel MG, Sather HN, et al.: Clinical significance of translocation t(1;19) in childhood
acute lymphoblastic leukemia in the context of contemporary therapies: a report from the
Children's Cancer Group. J Clin Oncol 16 (2): 527-35, 1998. [PUBMED A bstract]
75. Koehler M, Behm FG, Shuster J, et al.: Transitional pre-B-cell acute lymphoblastic leukemia of
childhood is associated with favorable prognostic clinical features and an excellent outcome: a
Pediatric Oncology Group study. Leukemia 7 (12): 2064-8, 1993. [PUBMED A bstract]
76. Attarbaschi A, Mann G, Dworzak M, et al.: Mediastinal mass in childhood T-cell acute
lymphoblastic leukemia: significance and therapy response. Med Pediatr Oncol 39 (6): 558-65,
77. Armstrong SA, Look AT: Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol 23 (26):
78. Karrman K, Forestier E, Heyman M, et al.: Clinical and cytogenetic features of a population-based
consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias: rare T-cell receptor gene
rearrangements are associated with poor outcome. Genes Chromosomes Cancer 48 (9): 795-805,
79. Bergeron J, Clappier E, Radford I, et al.: Prognostic and oncogenic relevance of TLX1/HOX11
expression level in T-ALLs. Blood 110 (7): 2324-30, 2007. [PUBMED A bstract]
80. van Grotel M, Meijerink JP, Beverloo HB, et al.: The outcome of molecular-cytogenetic subgroups
in pediatric T-cell acute lymphoblastic leukemia: a retrospective study of patients treated
according to DCOG or COALL protocols. Haematologica 91 (9): 1212-21, 2006. [PUBMED A bstract]
81. Cav H, Suciu S, Preudhomme C, et al.: Clinical significance of HOX11L2 expression linked to
t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies:
results of EORTC studies 58881 and 58951. Blood 103 (2): 442-50, 2004. [PUBMED A bstract]
82. Baak U, Gkbuget N, Orawa H, et al.: Thymic adult T-cell acute lymphoblastic leukemia stratified
in standard- and high-risk group by aberrant HOX11L2 expression: experience of the German
multicenter ALL study group. Leukemia 22 (6): 1154-60, 2008. [PUBMED A bstract]
83. Ferrando AA, Neuberg DS, Dodge RK, et al.: Prognostic importance of TLX1 (HOX11) oncogene
expression in adults with T-cell acute lymphoblastic leukaemia. Lancet 363 (9408): 535-6, 2004.
[PUBMED A bstract]
84. Weng AP, Ferrando AA, Lee W, et al.: Activating mutations of NOTCH1 in human T cell acute
lymphoblastic leukemia. Science 306 (5694): 269-71, 2004. [PUBMED A bstract]
85. Breit S, Stanulla M, Flohr T, et al.: Activating NOTCH1 mutations predict favorable early treatment
response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood 108
(4): 1151-7, 2006. [PUBMED A bstract]
86. Kox C, Zimmermann M, Stanulla M, et al.: The favorable effect of activating NOTCH1 receptor
mutations on long-term outcome in T-ALL patients treated on the ALL-BFM 2000 protocol can be
separated from FBXW7 loss of function. Leukemia 24 (12): 2005-13, 2010. [PUBMED A bstract]
87. Jenkinson S, Koo K, Mansour MR, et al.: Impact of NOTCH1/FBXW7 mutations on outcome in
pediatric T-cell acute lymphoblastic leukemia patients treated on the MRC UKALL 2003 trial.
Leukemia 27 (1): 41-7, 2013. [PUBMED A bstract]
88. Larson Gedman A, Chen Q, Kugel Desmoulin S, et al.: The impact of NOTCH1, FBW7 and PTEN
mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia:
a report from the Children's Oncology Group. Leukemia 23 (8): 1417-25, 2009. [PUBMED A bstract]
89. Zuurbier L, Homminga I, Calvert V, et al.: NOTCH1 and/or FBXW7 mutations predict for initial
good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic
leukemia patients treated on DCOG or COALL protocols. Leukemia 24 (12): 2014-22, 2010.
[PUBMED A bstract]
90. Clappier E, Collette S, Grardel N, et al.: NOTCH1 and FBXW7 mutations have a favorable impact on
early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic
leukemia (T-ALL) treated on EORTC trials 58881 and 58951. Leukemia 24 (12): 2023-31, 2010.
[PUBMED A bstract]
91. Burmeister T, Gkbuget N, Reinhardt R, et al.: NUP214-ABL1 in adult T-ALL: the GMALL study
group experience. Blood 108 (10): 3556-9, 2006. [PUBMED A bstract]
92. Graux C, Stevens-Kroef M, Lafage M, et al.: Heterogeneous patterns of amplification of the

NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia. Leukemia 23 (1): 125-33, 2009.
[PUBMED A bstract]
93. Hagemeijer A, Graux C: ABL1 rearrangements in T-cell acute lymphoblastic leukemia. Genes
Chromosomes Cancer 49 (4): 299-308, 2010. [PUBMED A bstract]
94. Quints-Cardama A, Tong W, Manshouri T, et al.: Activity of tyrosine kinase inhibitors against
human NUP214-ABL1-positive T cell malignancies. Leukemia 22 (6): 1117-24, 2008. [PUBMED
A bstract]
95. Clarke S, O'Reilly J, Romeo G, et al.: NUP214-ABL1 positive T-cell acute lymphoblastic leukemia
patient shows an initial favorable response to imatinib therapy post relapse. Leuk Res 35 (7): e131-
96. Deenik W, Beverloo HB, van der Poel-van de Luytgaarde SC, et al.: Rapid complete cytogenetic
remission after upfront dasatinib monotherapy in a patient with a NUP214-ABL1-positive T-cell

acute lymphoblastic leukemia. Leukemia 23 (3): 627-9, 2009. [PUBMED A bstract]
97. Crombet O, Lastrapes K, Zieske A, et al.: Complete morphologic and molecular remission after
introduction of dasatinib in the treatment of a pediatric patient with t-cell acute lymphoblastic
leukemia and ABL1 amplification. Pediatr Blood Cancer 59 (2): 333-4, 2012. [PUBMED A bstract]
98. Zhang J, Ding L, Holmfeldt L, et al.: The genetic basis of early T-cell precursor acute lymphoblastic
leukaemia. Nature 481 (7380): 157-63, 2012. [PUBMED A bstract]
99. Ma M, Wang X, Tang J, et al.: Early T-cell precursor leukemia: a subtype of high risk childhood
acute lymphoblastic leukemia. Front Med 6 (4): 416-20, 2012. [PUBMED A bstract]
100. Inukai T, Kiyokawa N, Campana D, et al.: Clinical significance of early T-cell precursor acute
lymphoblastic leukaemia: results of the Tokyo Children's Cancer Study Group Study L99-15. Br J
Haematol 156 (3): 358-65, 2012. [PUBMED A bstract]
101. Gutierrez A, Dahlberg SE, Neuberg DS, et al.: Absence of biallelic TCRgamma deletion predicts
early treatment failure in pediatric T-cell acute lymphoblastic leukemia. J Clin Oncol 28 (24): 3816-
102. Yang YL, Hsiao CC, Chen HY, et al.: Absence of biallelic TCR deletion predicts induction failure
and poorer outcomes in childhood T-cell acute lymphoblastic leukemia. Pediatr Blood Cancer 58
(6): 846-51, 2012. [PUBMED A bstract]
103. Pui CH, Rubnitz JE, Hancock ML, et al.: Reappraisal of the clinical and biologic significance of
myeloid-associated antigen expression in childhood acute lymphoblastic leukemia. J Clin Oncol 16
(12): 3768-73, 1998. [PUBMED A bstract]
104. Uckun FM, Sather HN, Gaynon PS, et al.: Clinical features and treatment outcome of children with
myeloid antigen positive acute lymphoblastic leukemia: a report from the Children's Cancer Group.
Blood 90 (1): 28-35, 1997. [PUBMED A bstract]
105. Gerr H, Zimmermann M, Schrappe M, et al.: Acute leukaemias of ambiguous lineage in children:
characterization, prognosis and therapy recommendations. Br J Haematol 149 (1): 84-92, 2010.
[PUBMED A bstract]
106. Rubnitz JE, Onciu M, Pounds S, et al.: Acute mixed lineage leukemia in children: the experience of
St Jude Children's Research Hospital. Blood 113 (21): 5083-9, 2009. [PUBMED A bstract]
107. Al-Seraihy AS, Owaidah TM, Ayas M, et al.: Clinical characteristics and outcome of children with
biphenotypic acute leukemia. Haematologica 94 (12): 1682-90, 2009. [PUBMED A bstract]
108. Bene MC, Castoldi G, Knapp W, et al.: Proposals for the immunological classification of acute
leukemias. European Group for the Immunological Characterization of Leukemias (EGIL).
109. Vardiman JW, Thiele J, Arber DA, et al.: The 2008 revision of the World Health Organization
(WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes.
110. Borowitz MJ, Bn MC, Harris NL: Acute leukaemias of ambiguous lineage. In: Swerdlow SH,
Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid
Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 150-5.
111. Matutes E, Pickl WF, Van't Veer M, et al.: Mixed-phenotype acute leukemia: clinical and laboratory
features and outcome in 100 patients defined according to the WHO 2008 classification. Blood 117
(11): 3163-71, 2011. [PUBMED A bstract]
112. Moorman AV, Ensor HM, Richards SM, et al.: Prognostic effect of chromosomal abnormalities in
childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research
Council ALL97/99 randomised trial. Lancet Oncol 11 (5): 429-38, 2010. [PUBMED A bstract]
113. Paulsson K, Johansson B: High hyperdiploid childhood acute lymphoblastic leukemia. Genes
Chromosomes Cancer 48 (8): 637-60, 2009. [PUBMED A bstract]
114. Aric M, Valsecchi MG, Rizzari C, et al.: Long-term results of the AIEOP-ALL-95 Trial for
Childhood Acute Lymphoblastic Leukemia: insight on the prognostic value of DNA index in the
framework of Berlin-Frankfurt-Muenster based chemotherapy. J Clin Oncol 26 (2): 283-9, 2008.
[PUBMED A bstract]
115. Synold TW, Relling MV, Boyett JM, et al.: Blast cell methotrexate-polyglutamate accumulation in
vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. J Clin
Invest 94 (5): 1996-2001, 1994. [PUBMED A bstract]
116. Moorman AV, Richards SM, Martineau M, et al.: Outcome heterogeneity in childhood high-
hyperdiploid acute lymphoblastic leukemia. Blood 102 (8): 2756-62, 2003. [PUBMED A bstract]
117. Sutcliffe MJ, Shuster JJ, Sather HN, et al.: High concordance from independent studies by the
Children's Cancer Group (CCG) and Pediatric Oncology Group (POG) associating favorable
prognosis with combined trisomies 4, 10, and 17 in children with NCI Standard-Risk B-precursor
Acute Lymphoblastic Leukemia: a Children's Oncology Group (COG) initiative. Leukemia 19 (5):
118. Harris MB, Shuster JJ, Carroll A, et al.: Trisomy of leukemic cell chromosomes 4 and 10 identifies
children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment
failure: a Pediatric Oncology Group study. Blood 79 (12): 3316-24, 1992. [PUBMED A bstract]
119. Heerema NA, Harbott J, Galimberti S, et al.: Secondary cytogenetic aberrations in childhood
Philadelphia chromosome positive acute lymphoblastic leukemia are nonrandom and may be
associated with outcome. Leukemia 18 (4): 693-702, 2004. [PUBMED A bstract]
120. Nachman JB, Heerema NA, Sather H, et al.: Outcome of treatment in children with hypodiploid
acute lymphoblastic leukemia. Blood 110 (4): 1112-5, 2007. [PUBMED A bstract]
121. Raimondi SC, Zhou Y, Shurtleff SA, et al.: Near-triploidy and near-tetraploidy in childhood acute
lymphoblastic leukemia: association with B-lineage blast cells carrying the ETV6-RUNX1 fusion, T-
lineage immunophenotype, and favorable outcome. Cancer Genet Cytogenet 169 (1): 50-7, 2006.
[PUBMED A bstract]
122. Attarbaschi A, Mann G, Knig M, et al.: Incidence and relevance of secondary chromosome
abnormalities in childhood TEL/AML1+ acute lymphoblastic leukemia: an interphase FISH
analysis. Leukemia 18 (10): 1611-6, 2004. [PUBMED A bstract]
123. Lemez P, Attarbaschi A, Bn MC, et al.: Childhood near-tetraploid acute lymphoblastic leukemia:
an EGIL study on 36 cases. Eur J Haematol 85 (4): 300-8, 2010. [PUBMED A bstract]
124. Harrison CJ, Moorman AV, Broadfield ZJ, et al.: Three distinct subgroups of hypodiploidy in acute
lymphoblastic leukaemia. Br J Haematol 125 (5): 552-9, 2004. [PUBMED A bstract]
125. Holmfeldt L, Wei L, Diaz-Flores E, et al.: The genomic landscape of hypodiploid acute
126. Rubnitz JE, Wichlan D, Devidas M, et al.: Prospective analysis of TEL gene rearrangements in
childhood acute lymphoblastic leukemia: a Children's Oncology Group study. J Clin Oncol 26 (13):
127. Kanerva J, Saarinen-Pihkala UM, Niini T, et al.: Favorable outcome in 20-year follow-up of
children with very-low-risk ALL and minimal standard therapy, with special reference to TEL-
AML1 fusion. Pediatr Blood Cancer 42 (1): 30-5, 2004. [PUBMED A bstract]
128. Aldrich MC, Zhang L, Wiemels JL, et al.: Cytogenetics of Hispanic and White children with acute
lymphoblastic leukemia in California. Cancer Epidemiol Biomarkers Prev 15 (3): 578-81, 2006.
[PUBMED A bstract]
129. Loh ML, Goldwasser MA, Silverman LB, et al.: Prospective analysis of TEL/AML1-positive patients
treated on Dana-Farber Cancer Institute Consortium Protocol 95-01. Blood 107 (11): 4508-13,
130. Borowitz MJ, Devidas M, Hunger SP, et al.: Clinical significance of minimal residual disease in
childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a
Children's Oncology Group study. Blood 111 (12): 5477-85, 2008. [PUBMED A bstract]
131. Madzo J, Zuna J, Muzkov K, et al.: Slower molecular response to treatment predicts poor
outcome in patients with TEL/AML1 positive acute lymphoblastic leukemia: prospective real-time
quantitative reverse transcriptase-polymerase chain reaction study. Cancer 97 (1): 105-13, 2003.
[PUBMED A bstract]
132. Bhojwani D, Pei D, Sandlund JT, et al.: ETV6-RUNX1-positive childhood acute lymphoblastic
leukemia: improved outcome with contemporary therapy. Leukemia 26 (2): 265-70, 2012. [PUBMED
A bstract]
133. Forestier E, Heyman M, Andersen MK, et al.: Outcome of ETV6/RUNX1-positive childhood acute
lymphoblastic leukaemia in the NOPHO-ALL-1992 protocol: frequent late relapses but good overall
survival. Br J Haematol 140 (6): 665-72, 2008. [PUBMED A bstract]
134. Seeger K, Stackelberg AV, Taube T, et al.: Relapse of TEL-AML1--positive acute lymphoblastic
leukemia in childhood: a matched-pair analysis. J Clin Oncol 19 (13): 3188-93, 2001. [PUBMED
A bstract]
135. Gandemer V, Chevret S, Petit A, et al.: Excellent prognosis of late relapses of ETV6/RUNX1-
positive childhood acute lymphoblastic leukemia: lessons from the FRALLE 93 protocol.
Haematologica 97 (11): 1743-50, 2012. [PUBMED A bstract]
136. Zuna J, Ford AM, Peham M, et al.: TEL deletion analysis supports a novel view of relapse in
childhood acute lymphoblastic leukemia. Clin Cancer Res 10 (16): 5355-60, 2004. [PUBMED A bstract]
137. van Delft FW, Horsley S, Colman S, et al.: Clonal origins of relapse in ETV6-RUNX1 acute
lymphoblastic leukemia. Blood 117 (23): 6247-54, 2011. [PUBMED A bstract]
138. Aric M, Schrappe M, Hunger SP, et al.: Clinical outcome of children with newly diagnosed
Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005.
139. Schrappe M, Aric M, Harbott J, et al.: Philadelphia chromosome-positive (Ph+) childhood acute
lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable
treatment outcome. Blood 92 (8): 2730-41, 1998. [PUBMED A bstract]
140. Ribeiro RC, Broniscer A, Rivera GK, et al.: Philadelphia chromosome-positive acute lymphoblastic
leukemia in children: durable responses to chemotherapy associated with low initial white blood
cell counts. Leukemia 11 (9): 1493-6, 1997. [PUBMED A bstract]
141. Biondi A, Schrappe M, De Lorenzo P, et al.: Imatinib after induction for treatment of children and
adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a
randomised, open-label, intergroup study. Lancet Oncol 13 (9): 936-45, 2012. [PUBMED A bstract]
142. Schultz KR, Bowman WP, Aledo A, et al.: Improved early event-free survival with imatinib in
Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group
143. Johansson B, Moorman AV, Haas OA, et al.: Hematologic malignancies with t(4;11)(q21;q23)--a
cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases. European 11q23
Workshop participants. Leukemia 12 (5): 779-87, 1998. [PUBMED A bstract]
144. Raimondi SC, Peiper SC, Kitchingman GR, et al.: Childhood acute lymphoblastic leukemia with
chromosomal breakpoints at 11q23. Blood 73 (6): 1627-34, 1989. [PUBMED A bstract]
145. Harrison CJ, Moorman AV, Barber KE, et al.: Interphase molecular cytogenetic screening for
chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic
leukaemia: a UK Cancer Cytogenetics Group Study. Br J Haematol 129 (4): 520-30, 2005. [PUBMED
A bstract]
146. Pui CH, Gaynon PS, Boyett JM, et al.: Outcome of treatment in childhood acute lymphoblastic
leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 359 (9321): 1909-15,
147. Rubnitz JE, Camitta BM, Mahmoud H, et al.: Childhood acute lymphoblastic leukemia with the
MLL-ENL fusion and t(11;19)(q23;p13.3) translocation. J Clin Oncol 17 (1): 191-6, 1999. [PUBMED
A bstract]
148. Pui CH, Sandlund JT, Pei D, et al.: Results of therapy for acute lymphoblastic leukemia in black and
white children. JAMA 290 (15): 2001-7, 2003. [PUBMED A bstract]
149. Crist WM, Carroll AJ, Shuster JJ, et al.: Poor prognosis of children with pre-B acute lymphoblastic
leukemia is associated with the t(1;19)(q23;p13): a Pediatric Oncology Group study. Blood 76 (1):
150. Andersen MK, Autio K, Barbany G, et al.: Paediatric B-cell precursor acute lymphoblastic
leukaemia with t(1;19)(q23;p13): clinical and cytogenetic characteristics of 47 cases from the
Nordic countries treated according to NOPHO protocols. Br J Haematol 155 (2): 235-43, 2011.
[PUBMED A bstract]
151. Jeha S, Pei D, Raimondi SC, et al.: Increased risk for CNS relapse in pre-B cell leukemia with the
t(1;19)/TCF3-PBX1. Leukemia 23 (8): 1406-9, 2009. [PUBMED A bstract]
152. Harvey RC, Mullighan CG, Wang X, et al.: Identification of novel cluster groups in pediatric high-
risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with
genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood 116 (23):
153. Zhang J, Mullighan CG, Harvey RC, et al.: Key pathways are frequently mutated in high-risk
childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 118
(11): 3080-7, 2011. [PUBMED A bstract]
154. Hunger SP, Raetz EA, Loh ML, et al.: Improving outcomes for high-risk ALL: translating new
discoveries into clinical care. Pediatr Blood Cancer 56 (6): 984-93, 2011. [PUBMED A bstract]
155. Chen IM, Harvey RC, Mullighan CG, et al.: Outcome modeling with CRLF2, IKZF1, JAK, and
minimal residual disease in pediatric acute lymphoblastic leukemia: a Children's Oncology Group
study. Blood 119 (15): 3512-22, 2012. [PUBMED A bstract]
156. Pui CH, Mullighan CG, Evans WE, et al.: Pediatric acute lymphoblastic leukemia: where are we
going and how do we get there? Blood 120 (6): 1165-74, 2012. [PUBMED A bstract]
157. Roberts KG, Morin RD, Zhang J, et al.: Genetic alterations activating kinase and cytokine receptor
signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 22 (2): 153-66, 2012. [PUBMED
A bstract]
158. Mullighan CG: Molecular genetics of B-precursor acute lymphoblastic leukemia. J Clin Invest 122
(10): 3407-15, 2012. [PUBMED A bstract]
159. Moorman AV, Richards SM, Robinson HM, et al.: Prognosis of children with acute lymphoblastic
leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21). Blood 109 (6):
160. Attarbaschi A, Mann G, Panzer-Grmayer R, et al.: Minimal residual disease values discriminate
between low and high relapse risk in children with B-cell precursor acute lymphoblastic leukemia
and an intrachromosomal amplification of chromosome 21: the Austrian and German acute
lymphoblastic leukemia Berlin-Frankfurt-Munster (ALL-BFM) trials. J Clin Oncol 26 (18): 3046-
161. Mullighan CG, Goorha S, Radtke I, et al.: Genome-wide analysis of genetic alterations in acute
lymphoblastic leukaemia. Nature 446 (7137): 758-64, 2007. [PUBMED A bstract]
162. Schwab CJ, Chilton L, Morrison H, et al.: Genes commonly deleted in childhood B-cell precursor
acute lymphoblastic leukemia: association with cytogenetics and clinical features. Haematologica
98 (7): 1081-8, 2013. [PUBMED A bstract]
163. Mullighan CG, Miller CB, Radtke I, et al.: BCR-ABL1 lymphoblastic leukaemia is characterized by
the deletion of Ikaros. Nature 453 (7191): 110-4, 2008. [PUBMED A bstract]
164. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al.: A subtype of childhood acute
lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet
Oncol 10 (2): 125-34, 2009. [PUBMED A bstract]
165. Mullighan CG, Su X, Zhang J, et al.: Deletion of IKZF1 and prognosis in acute lymphoblastic
leukemia. N Engl J Med 360 (5): 470-80, 2009. [PUBMED A bstract]
166. Krentz S, Hof J, Mendioroz A, et al.: Prognostic value of genetic alterations in children with first
bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia. Leukemia 27 (2):
167. Feng J, Tang Y: Prognostic significance of IKZF1 alteration status in pediatric B-lineage acute
lymphoblastic leukemia: a meta-analysis. Leuk Lymphoma 54 (4): 889-91, 2013. [PUBMED A bstract]
168. Drge P, Meissner B, Zimmermann M, et al.: IKZF1 deletion is an independent predictor of outcome
in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol.
169. van der Veer A, Waanders E, Pieters R, et al.: Independent prognostic value of BCR-ABL1-like
signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor
ALL. Blood 122 (15): 2622-9, 2013. [PUBMED A bstract]
170. Cario G, Zimmermann M, Romey R, et al.: Presence of the P2RY8-CRLF2 rearrangement is

associated with a poor prognosis in non-high-risk precursor B-cell acute lymphoblastic leukemia in
children treated according to the ALL-BFM 2000 protocol. Blood 115 (26): 5393-7, 2010. [PUBMED
A bstract]
171. Ensor HM, Schwab C, Russell LJ, et al.: Demographic, clinical, and outcome features of children
with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical
trial. Blood 117 (7): 2129-36, 2011. [PUBMED A bstract]
172. Harvey RC, Mullighan CG, Chen IM, et al.: Rearrangement of CRLF2 is associated with mutation of
JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-
progenitor acute lymphoblastic leukemia. Blood 115 (26): 5312-21, 2010. [PUBMED A bstract]
173. Loh ML, Zhang J, Harvey RC, et al.: Tyrosine kinome sequencing of pediatric acute lymphoblastic
leukemia: a report from the Children's Oncology Group TARGET Project. Blood 121 (3): 485-8,
174. Palmi C, Vendramini E, Silvestri D, et al.: Poor prognosis for P2RY8-CRLF2 fusion but not for
CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic
leukemia. Leukemia 26 (10): 2245-53, 2012. [PUBMED A bstract]
175. Davies SM, Bhatia S, Ross JA, et al.: Glutathione S-transferase genotypes, genetic susceptibility,
and outcome of therapy in childhood acute lymphoblastic leukemia. Blood 100 (1): 67-71, 2002.
[PUBMED A bstract]
176. Krajinovic M, Costea I, Chiasson S: Polymorphism of the thymidylate synthase gene and outcome
of acute lymphoblastic leukaemia. Lancet 359 (9311): 1033-4, 2002. [PUBMED A bstract]
177. Krajinovic M, Lemieux-Blanchard E, Chiasson S, et al.: Role of polymorphisms in MTHFR and

MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J 4
(1): 66-72, 2004. [PUBMED A bstract]
178. Schmiegelow K, Forestier E, Kristinsson J, et al.: Thiopurine methyltransferase activity is related to

the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92
study. Leukemia 23 (3): 557-64, 2009. [PUBMED A bstract]
179. Relling MV, Hancock ML, Boyett JM, et al.: Prognostic importance of 6-mercaptopurine dose
intensity in acute lymphoblastic leukemia. Blood 93 (9): 2817-23, 1999. [PUBMED A bstract]
180. Stanulla M, Schaeffeler E, Flohr T, et al.: Thiopurine methyltransferase (TPMT) genotype and
early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. JAMA
293 (12): 1485-9, 2005. [PUBMED A bstract]
181. Yang JJ, Cheng C, Yang W, et al.: Genome-wide interrogation of germline genetic variation
associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 301 (4):
182. Gregers J, Christensen IJ, Dalhoff K, et al.: The association of reduced folate carrier 80G>A
polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome
21 copy number. Blood 115 (23): 4671-7, 2010. [PUBMED A bstract]
183. Radtke S, Zolk O, Renner B, et al.: Germline genetic variations in methotrexate candidate genes are
associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic
leukemia. Blood 121 (26): 5145-53, 2013. [PUBMED A bstract]
184. Relling MV, Dervieux T: Pharmacogenetics and cancer therapy. Nat Rev Cancer 1 (2): 99-108,
185. van Dongen JJ, Seriu T, Panzer-Grmayer ER, et al.: Prognostic value of minimal residual disease
in acute lymphoblastic leukaemia in childhood. Lancet 352 (9142): 1731-8, 1998. [PUBMED A bstract]
186. Zhou J, Goldwasser MA, Li A, et al.: Quantitative analysis of minimal residual disease predicts
relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol
95-01. Blood 110 (5): 1607-11, 2007. [PUBMED A bstract]
187. Coustan-Smith E, Sancho J, Hancock ML, et al.: Use of peripheral blood instead of bone marrow to
monitor residual disease in children with acute lymphoblastic leukemia. Blood 100 (7): 2399-402,
188. Yamaji K, Okamoto T, Yokota S, et al.: Minimal residual disease-based augmented therapy in
childhood acute lymphoblastic leukemia: a report from the Japanese Childhood Cancer and
Leukemia Study Group. Pediatr Blood Cancer 55 (7): 1287-95, 2010. [PUBMED A bstract]
189. Marshall GM, Dalla Pozza L, Sutton R, et al.: High-risk childhood acute lymphoblastic leukemia in
first remission treated with novel intensive chemotherapy and allogeneic transplantation.
190. Conter V, Bartram CR, Valsecchi MG, et al.: Molecular response to treatment redefines all
prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia:
results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 115 (16): 3206-14, 2010.
[PUBMED A bstract]
191. Stow P, Key L, Chen X, et al.: Clinical significance of low levels of minimal residual disease at the
end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood 115 (23):
192. Basso G, Veltroni M, Valsecchi MG, et al.: Risk of relapse of childhood acute lymphoblastic
leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow.
193. Panzer-Grmayer ER, Schneider M, Panzer S, et al.: Rapid molecular response during early
induction chemotherapy predicts a good outcome in childhood acute lymphoblastic leukemia.
194. Coustan-Smith E, Sancho J, Behm FG, et al.: Prognostic importance of measuring early clearance of
leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood 100 (1): 52-8,
195. Schrappe M, Valsecchi MG, Bartram CR, et al.: Late MRD response determines relapse risk overall
and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood 118 (8):
196. Biojone E, Queirz Rde P, Valera ET, et al.: Minimal residual disease in cerebrospinal fluid at
diagnosis: a more intensive treatment protocol was able to eliminate the adverse prognosis in
children with acute lymphoblastic leukemia. Leuk Lymphoma 53 (1): 89-95, 2012. [PUBMED A bstract]
197. Vora A, Goulden N, Wade R, et al.: Treatment reduction for children and young adults with low-
risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a
randomised controlled trial. Lancet Oncol 14 (3): 199-209, 2013. [PUBMED A bstract]
198. Gaynon PS, Desai AA, Bostrom BC, et al.: Early response to therapy and outcome in childhood
acute lymphoblastic leukemia: a review. Cancer 80 (9): 1717-26, 1997. [PUBMED A bstract]
199. Borowitz MJ, Wood BL, Devidas M, et al.: Assessment of end induction minimal residual disease
(MRD) in childhood B precursor acute lymphoblastic leukemia (ALL) to eliminate the need for day
14 marrow examination: A Childrens Oncology Group study. [Abstract] J Clin Oncol 31 (Suppl 15):
A-10001, 2013. Also available online. Last accessed April 04, 2014.

201. Griffin TC, Shuster JJ, Buchanan GR, et al.: Slow disappearance of peripheral blood blasts is an
adverse prognostic factor in childhood T cell acute lymphoblastic leukemia: a Pediatric Oncology
Group study. Leukemia 14 (5): 792-5, 2000. [PUBMED A bstract]
202. Volejnikova J, Mejstrikova E, Valova T, et al.: Minimal residual disease in peripheral blood at day
15 identifies a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with superior
prognosis. Haematologica 96 (12): 1815-21, 2011. [PUBMED A bstract]
203. Schrappe M, Hunger SP, Pui CH, et al.: Outcomes after induction failure in childhood acute
lymphoblastic leukemia. N Engl J Med 366 (15): 1371-81, 2012. [PUBMED A bstract]
204. Silverman LB, Gelber RD, Young ML, et al.: Induction failure in acute lymphoblastic leukemia of
childhood. Cancer 85 (6): 1395-404, 1999. [PUBMED A bstract]
205. Oudot C, Auclerc MF, Levy V, et al.: Prognostic factors for leukemic induction failure in children
with acute lymphoblastic leukemia and outcome after salvage therapy: the FRALLE 93 study. J Clin
208. Balduzzi A, Valsecchi MG, Uderzo C, et al.: Chemotherapy versus allogeneic transplantation for
very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison
by genetic randomisation in an international prospective study. Lancet 366 (9486): 635-42, 2005
Aug 20-26. [PUBMED A bstract]
209. Schrauder A, Reiter A, Gadner H, et al.: Superiority of allogeneic hematopoietic stem-cell

transplantation compared with chemotherapy alone in high-risk childhood T-cell acute
lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol 24 (36): 5742-9, 2006.
[PUBMED A bstract]
210. Ribera JM, Ortega JJ, Oriol A, et al.: Comparison of intensive chemotherapy, allogeneic, or
autologous stem-cell transplantation as postremission treatment for children with very high risk
acute lymphoblastic leukemia: PETHEMA ALL-93 Trial. J Clin Oncol 25 (1): 16-24, 2007. [PUBMED
A bstract]
Treatment Option Overview for Childhood ALL
Children with acute lymphoblastic leukemia (ALL) should be cared for at a center with specialized
expertise in pediatric cancer.[1] Treatment planning by a multidisciplinary team of pediatric cancer
specialists with experience and expertise in treating leukemias of childhood is required to determine and
implement optimum treatment.
Treatment of childhood ALL typically involves chemotherapy given for 2 to 3 years. Since
myelosuppression and generalized immunosuppression are anticipated consequences of leukemia and
chemotherapy treatment, patients must be closely monitored at diagnosis and during treatment.
Adequate facilities must be immediately available both for hematologic support and for the treatment of
infections and other complications throughout all phases of therapy. Approximately 1% to 3% of patients
die during induction therapy and another 1% to 3% die during the initial remission from treatment-related
complications.[2,3]
Clinical trials are generally available for children with ALL, with specific protocols designed for children
at standard (low) risk of treatment failure and for children at higher risk of treatment failure. Clinical
trials for children with ALL are generally designed to compare therapy that is currently accepted as
standard for a particular risk group with a potentially better treatment approach that may improve
survival outcome and/or diminish toxicities associated with the standard treatment regimen. Many of the
therapeutic innovations that produced increased survival rates in children with ALL were established
through clinical trials, and it is appropriate for children and adolescents with ALL to be offered
participation in a clinical trial.
Risk-based treatment assignment is an important therapeutic strategy utilized for children with ALL. This
approach allows children who historically have a very good outcome to be treated with less intensive
therapy and to be spared more toxic treatments, while allowing children with a historically lower
probability of long-term survival to receive stronger therapy that may increase their chance of cure.
(Refer to the Risk-based Treatment Assignment section of this summary for more information about a
number of clinical and laboratory features that have demonstrated prognostic value.)
Phases of Therapy
Treatment for children with ALL is typically divided as follows:
1. Remission induction (at the time of diagnosis).
2. Postinduction therapy (after achieving complete remission).

Consolidation/intensification therapy.
Maintenance or continuation therapy.
Sanctuary Sites
Historically, certain extramedullary sites have been considered sanctuary sites (i.e., anatomic spaces that
are poorly penetrated by many of the systemically administered chemotherapy agents typically used to
treat ALL). The two most important sanctuary sites in childhood ALL are the central nervous system
(CNS) and the testes. Successful treatment of ALL requires therapy that effectively addresses clinical or
subclinical involvement of leukemia in these extramedullary sanctuary sites.
Central nervous system (CNS)
Approximately 3% of patients have detectable CNS involvement by conventional criteria at diagnosis

(cerebrospinal fluid specimen with 5 WBC/L with lymphoblasts and/or the presence of cranial nerve
palsies). However, unless specific therapy is directed toward the CNS, the majority of children will
eventually develop overt CNS leukemia. CNS-directed treatments include intrathecal chemotherapy,
CNS-directed systemic chemotherapy, and cranial radiation; some or all of these are included in current
regimens for ALL. (Refer to the CNS-directed Therapy for Childhood Acute Lymphoblastic Leukemia
section of this summary for more information.)
T estes
Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males. In early ALL
trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial
therapy, however, the prognostic significance of initial testicular involvement is unclear.[4,5] The role of
radiation therapy for testicular involvement is also unclear. A study from St. Jude Children's Research
Hospital suggests that a good outcome can be achieved with aggressive conventional chemotherapy
without radiation.[4] The Children's Oncology Group has also adopted this strategy for boys with
testicular involvement that resolves completely during induction chemotherapy.
References
1. Corrigan JJ, Feig SA; American Academy of Pediatrics.: Guidelines for pediatric cancer centers.
Pediatrics 113 (6): 1833-5, 2004. [PUBMED A bstract]
2. Rubnitz JE, Lensing S, Zhou Y, et al.: Death during induction therapy and first remission of acute
leukemia in childhood: the St. Jude experience. Cancer 101 (7): 1677-84, 2004. [PUBMED A bstract]
3. Christensen MS, Heyman M, Mttnen M, et al.: Treatment-related death in childhood acute

lymphoblastic leukaemia in the Nordic countries: 1992-2001. Br J Haematol 131 (1): 50-8, 2005.
[PUBMED A bstract]
4. Hijiya N, Liu W, Sandlund JT, et al.: Overt testicular disease at diagnosis of childhood acute
lymphoblastic leukemia: lack of therapeutic role of local irradiation. Leukemia 19 (8): 1399-403,
5. Sirvent N, Suciu S, Bertrand Y, et al.: Overt testicular disease (OTD) at diagnosis is not associated
with a poor prognosis in childhood acute lymphoblastic leukemia: results of the EORTC CLG Study
58881. Pediatr Blood Cancer 49 (3): 344-8, 2007. [PUBMED A bstract]
Treatment for Newly Diagnosed Childhood ALL
Standard Treatment Options for Newly Diagnosed ALL
Standard treatment options for newly diagnosed childhood acute lymphoblastic leukemia (ALL) include
the following:
1. Chemotherapy.
Remission induction chemotherapy
The goal of the first phase of therapy (remission induction) is to induce a complete remission (CR). This
phase typically lasts 4 weeks. Overall, approximately 98% of patients with newly diagnosed B-precursor
ALL achieve CR by the end of this phase, with somewhat lower rates in patients with T-cell ALL or high
presenting leukocyte counts.[1-5]
Induction chemotherapy consists of the following drugs, with or without an anthracycline:
Vincristine.
Corticosteroid (prednisone or dexamethasone).
L-asparaginase.
The Children's Oncology Group (COG) protocols do not administer anthracycline during induction to
patients with National Cancer Institute standard-risk precursor B-cell ALL.
Patients treated by the following study groups receive an induction regimen with four or more drugs
regardless of presenting features:
Berlin-Frankfurt-Mnster Group in Europe.[1]

St. Jude Children's Research Hospital.[2]
Dana-Farber Cancer Institute ALL Consortium.[3]
The most common four-drug induction regimen is vincristine, corticosteroid (either dexamethasone or
prednisone), L-asparaginase, and either doxorubicin or daunorubicin.[6] In a randomized trial of
doxorubicin and daunorubicin during induction, there were no differences between these two agents in
early response measures, including reduction in peripheral blood blast counts during the first week of
therapy, day 15 marrow morphology, and end-induction minimal residual disease (MRD) levels.[6][Level
of evidence: 1iiDiv] Some studies have suggested that this more intensive induction regimen may result in
improved event-free survival (EFS) in patients presenting with high-risk features, but it may not be
necessary for favorable outcome provided that adequate postremission intensification therapy is
administered.[7,8] The COG reserves the use of a four-drug induction for patients with high-risk B-
precursor ALL and T-cell ALL.
Corticosteroid therapy
Many current regimens utilize dexamethasone instead of prednisone during remission induction and later
phases of therapy.
Evidence (dexamethasone):
1. The Children's Cancer Group conducted a randomized trial that compared dexamethasone and
prednisone in standard-risk ALL patients.
The trial reported that dexamethasone was associated with a superior EFS.[9]
2. Another randomized trial was conducted by the United Kingdom Medical Research Council.[10]
The trial demonstrated that dexamethasone was associated with a more favorable outcome
than prednisolone in all patient subgroups.
Patients who received dexamethasone had a significantly lower incidence of both central
nervous system (CNS) and non-CNS relapses than patients who received prednisolone.[10]
3. Other randomized trials did not confirm an EFS advantage with dexamethasone.[11,12]
The ratio of dexamethasone to prednisone dose used may influence outcome. Studies in which the
dexamethasone to prednisone ratio was 1:5 to 1:7 have shown a better result for dexamethasone, while
studies that used a 1:10 ratio have shown similar outcomes.[13]
While dexamethasone may be more effective than prednisone, data also suggest that dexamethasone may
be more toxic, especially in the context of more intensive induction regimens and in adolescents.[14]
Several reports indicate that dexamethasone may increase the frequency and severity of infections
and/or other complications in patients receiving anthracycline-containing induction regimens.[15,16]
The increased risk of infection with dexamethasone during the induction phase has not been noted with
three-drug induction regimens (vincristine, dexamethasone, and L-asparaginase).[10] Dexamethasone
appears to have a greater suppressive effect on short-term linear growth than prednisone [17] and has
been associated with a higher risk of osteonecrosis, especially in patients aged 10 years and older.
L-asparaginase
Several forms of L-asparaginase have been used in the treatment of children with ALL, including the
following:
PEG-L-asparaginase.
Erwinia L-asparaginase.
Native E. coli L-asparaginase.
Only PEG-L-asparaginase and Erwinia L-asparaginase are available in the United States. Native E. coli L-
asparaginase remains available in other countries.
PEG-L-asparaginase
PEG-L-asparaginase, a form of L-asparaginase in which the Escherichia coli-derived enzyme is modified

by the covalent attachment of polyethylene glycol, is the most common preparation used during both
induction and postinduction phases of treatment in newly diagnosed patients.
PEG-L-asparaginase may be given either intramuscularly (IM) or intravenously (IV).[18]

Pharmacokinetics and toxicity profiles are similar for IM and IV PEG-L-asparaginase administration.[18]
There is no evidence that IV administration of PEG-L-asparaginase is more toxic than IM administration.
[18,19]
PEG-L-asparaginase has a much longer serum half-life than native E. coli L-asparaginase, producing
prolonged asparagine depletion after a single injection.[20]
Serum asparaginase enzyme activity levels of more than 0.1 IU/mL have been associated with serum
asparagine depletion. Studies have shown that a single dose of PEG-L-asparaginase given either IM or IV
as part of multiagent induction results in serum enzyme activity (>0.1 IU/mL) in nearly all patients for at
least 2 to 3 weeks.[18,19,21]
Evidence (use of PEG-L-asparaginase instead of native E. coli L-asparaginase):
1. A randomized comparison of PEG-L-asparaginase versus native E. coli asparaginase was

conducted. Each agent was administered for a 30-week period after the achievement of CR.[22]
Similar outcome and similar rates of asparaginase-related toxicities were observed for both
groups of patients.
2. Another randomized trial of patients with standard-risk ALL assigned patients to receive either
PEG-L-asparaginase or native E. coli asparaginase in induction and each of two delayed
intensification courses.[21]
A single dose of PEG-L-asparaginase given in conjunction with vincristine and prednisone
during induction therapy appeared to have similar activity and toxicity as nine doses of IM
E. coli L-asparaginase (3 times a week for 3 weeks).[21]
The use of PEG-L-asparaginase was associated with more rapid blast clearance and a lower
incidence of neutralizing antibodies.
Patients with an allergic reaction to PEG-L-asparaginase should be switched to Erwinia L-asparaginase.
Erwinia L-asparaginase:
Erwinia L-asparaginase is typically used in patients who have experienced allergy to native E. coli or
PEG-L-asparaginase.
The half-life of Erwinia L-asparaginase (0.65 days) is much shorter than that of native E. coli (1.2 days) or
PEG-L-asparaginase (5.7 days).[20] If Erwinia L-asparaginase is utilized, the shorter half-life of the
Erwinia preparation requires more frequent administration to achieve adequate asparagine depletion.
Evidence (increased dose frequency of Erwinia L-asparaginase needed to achieve goal therapeutic effect):
1. In two studies, newly diagnosed patients were randomly assigned to receive the same schedule and
dosage of Erwinia L-asparaginase or E. coli L-asparaginase.[23,24]
Patients who received Erwinia L-asparaginase had a significantly worse EFS.
When administered more frequently (twice weekly), the use of Erwinia L-asparaginase did
not adversely impact EFS in patients who had experienced an allergic reaction to E. coli L-
asparaginase.[25]
2. A COG trial demonstrated that IM Erwinia L-asparaginase given three times a week to patients with
an allergy to PEG L-asparaginase leads to therapeutic serum asparaginase enzyme activity levels
(defined as a level 0.1 IU/mL). On that trial, 96% of children achieved a level of 0.1 IU/mL or
more at 2 days and 85% did so at 3 days.[26]
Response to remission induction chemotherapy

More than 95% of children with newly diagnosed ALL will achieve a CR within the first 4 weeks of
treatment. Of those who fail to achieve CR within the first 4 weeks, approximately one-half will
experience a toxic death during the induction phase (usually due to infection) and the other half will have
resistant disease (persistent morphologic leukemia).[24,27,28]; [29][Level of evidence: 3iA]
Patients with persistent leukemia at the end of the 4-week induction phase have a poor prognosis and may
benefit from an allogeneic hematopoietic stem cell transplant (HSCT) once CR is achieved.[30,31,4] In a
large retrospective series, the 10-year overall survival for patients with persistent leukemia was 32%.[32]
A trend for superior outcome with allogeneic HSCT compared with chemotherapy alone was observed in
patients with T-cell phenotype (any age) and B-precursor patients younger than 6 years. B-precursor ALL
patients who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities
(MLL translocation, BCR-ABL) had a relatively favorable prognosis, without any advantage in outcome
with the utilization of HSCT compared with chemotherapy alone.[32]
For patients who achieve CR, measures of the rapidity of blast clearance and MRD determinations have
important prognostic significance, particularly the following:
Morphologic persistence of marrow blasts at 7 and 14 days after starting multiagent remission
induction therapy has been correlated with higher relapse risk,[33] and has been used in the past by
the COG to risk-stratify patients. However, in multivariate analyses, when end-induction MRD is
included, these early marrow findings lose their prognostic significance.[34,35]
End-induction levels of submicroscopic MRD, assessed either by multiparameter flow cytometry

or polymerase chain reaction, strongly correlates with long-term outcome.[34,36-38]
Intensification of postinduction therapy for patients with high levels of end-induction MRD is
under investigation by many groups.
MRD levels earlier in induction (e.g., days 8 and 15) and at later postinduction time points (e.g.,
week 12 after starting therapy) have also been shown to have prognostic significance.[34,38-41]
(Refer to the Response to initial treatment affecting prognosis section of this summary for more
information.)
(Refer to the CNS-directed Therapy for Childhood Acute Lymphoblastic Leukemia section of this
summary for specific information about CNS therapy to prevent CNS relapse in children with newly
diagnosed ALL.)
untreated childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by
location, drug, intervention, and other criteria.
References

A bstract]
4. Oudot C, Auclerc MF, Levy V, et al.: Prognostic factors for leukemic induction failure in children
with acute lymphoblastic leukemia and outcome after salvage therapy: the FRALLE 93 study. J Clin
6. Escherich G, Zimmermann M, Janka-Schaub G, et al.: Doxorubicin or daunorubicin given upfront

in a therapeutic window are equally effective in children with newly diagnosed acute lymphoblastic
leukemia. A randomized comparison in trial CoALL 07-03. Pediatr Blood Cancer 60 (2): 254-7,
7. Tubergen DG, Gilchrist GS, O'Brien RT, et al.: Improved outcome with delayed intensification for
children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens
Cancer Group phase III trial. J Clin Oncol 11 (3): 527-37, 1993. [PUBMED A bstract]
8. Gaynon PS, Steinherz PG, Bleyer WA, et al.: Improved therapy for children with acute
lymphoblastic leukemia and unfavorable presenting features: a follow-up report of the Childrens
Cancer Group Study CCG-106. J Clin Oncol 11 (11): 2234-42, 1993. [PUBMED A bstract]
9. Bostrom BC, Sensel MR, Sather HN, et al.: Dexamethasone versus prednisone and daily oral versus
weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia:
a report from the Children's Cancer Group. Blood 101 (10): 3809-17, 2003. [PUBMED A bstract]
10. Mitchell CD, Richards SM, Kinsey SE, et al.: Benefit of dexamethasone compared with prednisolone
for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97
randomized trial. Br J Haematol 129 (6): 734-45, 2005. [PUBMED A bstract]
11. Igarashi S, Manabe A, Ohara A, et al.: No advantage of dexamethasone over prednisolone for the
outcome of standard- and intermediate-risk childhood acute lymphoblastic leukemia in the Tokyo
Children's Cancer Study Group L95-14 protocol. J Clin Oncol 23 (27): 6489-98, 2005. [PUBMED
A bstract]
12. De Moerloose B, Suciu S, Bertrand Y, et al.: Improved outcome with pulses of vincristine and
corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia
(ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3
trial 58951. Blood 116 (1): 36-44, 2010. [PUBMED A bstract]
13. McNeer JL, Nachman JB: The optimal use of steroids in paediatric acute lymphoblastic leukaemia:
no easy answers. Br J Haematol 149 (5): 638-52, 2010. [PUBMED A bstract]
14. Teuffel O, Kuster SP, Hunger SP, et al.: Dexamethasone versus prednisone for induction therapy in
childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Leukemia 25 (8):
15. Hurwitz CA, Silverman LB, Schorin MA, et al.: Substituting dexamethasone for prednisone
complicates remission induction in children with acute lymphoblastic leukemia. Cancer 88 (8):
16. Belgaumi AF, Al-Bakrah M, Al-Mahr M, et al.: Dexamethasone-associated toxicity during induction
chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of
daunomycin. Cancer 97 (11): 2898-903, 2003. [PUBMED A bstract]
17. Ahmed SF, Tucker P, Mushtaq T, et al.: Short-term effects on linear growth and bone turnover in
children randomized to receive prednisolone or dexamethasone. Clin Endocrinol (Oxf) 57 (2): 185-
18. Silverman LB, Supko JG, Stevenson KE, et al.: Intravenous PEG-asparaginase during remission
induction in children and adolescents with newly diagnosed acute lymphoblastic leukemia. Blood
115 (7): 1351-3, 2010. [PUBMED A bstract]
19. Rizzari C, Citterio M, Zucchetti M, et al.: A pharmacological study on pegylated asparaginase used
in front-line treatment of children with acute lymphoblastic leukemia. Haematologica 91 (1): 24-31,
20. Asselin BL, Whitin JC, Coppola DJ, et al.: Comparative pharmacokinetic studies of three
asparaginase preparations. J Clin Oncol 11 (9): 1780-6, 1993. [PUBMED A bstract]
21. Avramis VI, Sencer S, Periclou AP, et al.: A randomized comparison of native Escherichia coli
asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly
diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 99
(6): 1986-94, 2002. [PUBMED A bstract]
23. Duval M, Suciu S, Ferster A, et al.: Comparison of Escherichia coli-asparaginase with Erwinia-
asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized
European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3
trial. Blood 99 (8): 2734-9, 2002. [PUBMED A bstract]
25. Vrooman LM, Supko JG, Neuberg DS, et al.: Erwinia asparaginase after allergy to E. coli
asparaginase in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 54 (2): 199-205,
26. Salzer WL, Asselin B, Supko JG, et al.: Erwinia asparaginase achieves therapeutic activity after
pegaspargase allergy: a report from the Children's Oncology Group. Blood 122 (4): 507-14, 2013.
[PUBMED A bstract]
27. Pui CH, Sandlund JT, Pei D, et al.: Improved outcome for children with acute lymphoblastic
leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 104
(9): 2690-6, 2004. [PUBMED A bstract]
A bstract]
29. Prucker C, Attarbaschi A, Peters C, et al.: Induction death and treatment-related mortality in first
remission of children with acute lymphoblastic leukemia: a population-based analysis of the
Austrian Berlin-Frankfurt-Mnster study group. Leukemia 23 (7): 1264-9, 2009. [PUBMED A bstract]
31. Silverman LB, Gelber RD, Young ML, et al.: Induction failure in acute lymphoblastic leukemia of
childhood. Cancer 85 (6): 1395-404, 1999. [PUBMED A bstract]
33. Gaynon PS, Desai AA, Bostrom BC, et al.: Early response to therapy and outcome in childhood
acute lymphoblastic leukemia: a review. Cancer 80 (9): 1717-26, 1997. [PUBMED A bstract]
34. Borowitz MJ, Devidas M, Hunger SP, et al.: Clinical significance of minimal residual disease in
childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a
Children's Oncology Group study. Blood 111 (12): 5477-85, 2008. [PUBMED A bstract]
35. Borowitz MJ, Wood BL, Devidas M, et al.: Assessment of end induction minimal residual disease
(MRD) in childhood B precursor acute lymphoblastic leukemia (ALL) to eliminate the need for day
14 marrow examination: A Childrens Oncology Group study. [Abstract] J Clin Oncol 31 (Suppl 15):
A-10001, 2013. Also available online. Last accessed April 04, 2014.
36. van Dongen JJ, Seriu T, Panzer-Grmayer ER, et al.: Prognostic value of minimal residual disease
in acute lymphoblastic leukaemia in childhood. Lancet 352 (9142): 1731-8, 1998. [PUBMED A bstract]
37. Zhou J, Goldwasser MA, Li A, et al.: Quantitative analysis of minimal residual disease predicts
relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol
95-01. Blood 110 (5): 1607-11, 2007. [PUBMED A bstract]
38. Conter V, Bartram CR, Valsecchi MG, et al.: Molecular response to treatment redefines all
prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia:
results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 115 (16): 3206-14, 2010.
[PUBMED A bstract]
39. Coustan-Smith E, Sancho J, Behm FG, et al.: Prognostic importance of measuring early clearance of
leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood 100 (1): 52-8,
40. Basso G, Veltroni M, Valsecchi MG, et al.: Risk of relapse of childhood acute lymphoblastic
leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow.
41. Schrappe M, Valsecchi MG, Bartram CR, et al.: Late MRD response determines relapse risk overall
and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood 118 (8):
Postinduction Treatment for Childhood ALL
Standard Postinduction Treatment Options for Childhood ALL
Standard treatment options for consolidation/intensification and maintenance therapy include the
following:
1. Chemotherapy.
Central nervous system (CNS)-directed therapy is provided during premaintenance chemotherapy by all
groups. Some protocols (Childrens Oncology Group [COG], St. Jude Children's Research Hospital
[SJCRH], and Dana-Farber Cancer Institute [DFCI]) provide ongoing intrathecal chemotherapy during
maintenance, while others (Berlin-Frankfurt-Mnster [BFM]) do not. (Refer to the CNS-directed Therapy
for Childhood Acute Lymphoblastic Leukemia section of this summary for specific information about
CNS therapy to prevent CNS relapse in children with acute lymphoblastic leukemia [ALL] who are
receiving postinduction therapy.)
Consolidation/intensification therapy
Once complete remission (CR) has been achieved, systemic treatment in conjunction with CNS-directed
therapy follows. The intensity of the postinduction chemotherapy varies considerably depending on risk
group assignment, but all patients receive some form of intensification after the achievement of CR and
before beginning maintenance therapy.
The most commonly used intensification schema is the BFM backbone. This therapeutic backbone, first
introduced by the BFM clinical trials group, includes the following:[1]
1. An initial consolidation (sometimes referred to as Induction IB) immediately after the initial
induction phase. This phase includes cyclophosphamide, low-dose cytarabine, and a thiopurine
(mercaptopurine or thioguanine).
2. An interim maintenance phase, which includes multiple doses of either intermediate-dose or high-
dose methotrexate (15 g/m2 ) with leucovorin rescue or escalating doses of methotrexate (starting
dose 100 mg/m2 ) without leucovorin rescue.
3. Reinduction (or delayed intensification), which typically includes the same agents used during the
induction and initial consolidation phases.
4. Maintenance, typically consisting of mercaptopurine, low-dose methotrexate, and sometimes,

vincristine/steroid pulses.
This backbone has been adopted by many groups, including the COG. Variation of this backbone includes
the following:
Intensification for higher-risk patients by including additional interim maintenance and/or

reinduction phases and administering additional agents during some phases (e.g., vincristine and L-
asparaginase added to interim maintenance phases).
Elimination or truncation of some of the phases for lower-risk patients to minimize acute and long-
term toxicity.
Other clinical trial groups utilize a different therapeutic backbone during postinduction treatment phases:
Pediatric Oncology Group (POG): Protocols conducted by the former POG included intensification
with high-dose antimetabolite therapy (e.g., multiple doses of intermediate-dose or high-dose
methotrexate with leucovorin rescue), but no reinduction/delayed intensification phase.[2]
DFCI: The DFCI ALL Consortium protocols include 20 to 30 weeks of L-asparaginase beginning at
week 7 of therapy, given in conjunction with maintenance regimen (vincristine/dexamethasone
pulses, low-dose methotrexate, nightly mercaptopurine).[3] These protocols also do not include a
delayed intensification phase, but high-risk patients do receive additional doses of doxorubicin
(instead of methotrexate) during intensification.
SJCRH: SJCRH follows a BFM-backbone but intensifies maintenance for some patients using
rotating drug pairs.[4]
Standard-risk ALL
In children with standard-risk ALL, there has been an attempt to limit exposure to drugs such as
anthracyclines and alkylating agents that may be associated with an increased risk of late toxic effects.[5-
7] For regimens utilizing a BFM backbone (such as COG), a single reinduction/delayed intensification
phase, given with interim maintenance phases consisting of escalating doses of methotrexate (without
leucovorin rescue) and vincristine, have been associated with favorable outcomes.[8] Favorable
outcomes for standard-risk patients have also been reported by the POG, utilizing a limited number of
courses of intermediate-dose or high-dose methotrexate as consolidation followed by maintenance
therapy (without a reinduction phase),[6,9,10] and by the DFCI ALL Consortium utilizing multiple doses
of L-asparaginase (2030 weeks) as consolidation, without postinduction exposure to alkylating agents or
anthracyclines.[11,12]
Evidence (intensification for standard-risk ALL):
1. Clinical trials conducted in the 1980s and early 1990s demonstrated that the use of a delayed
intensification phase improved outcome for children with standard-risk ALL treated with regimens
using a BFM backbone.[13-15] The delayed intensification phase on such regimens, including those
of the COG, consists of a 3-week reinduction (including anthracycline) and reconsolidation
containing cyclophosphamide, cytarabine, and 6-thioguanine given approximately 3 months after
remission is achieved.[13,16,17]
2. A Children's Cancer Group study (CCG-1991/COG-1991) for standard-risk ALL utilized

dexamethasone for induction and a second delayed intensification phase. This study also compared
escalating intravenous (IV) methotrexate (without leucovorin rescue) in conjunction with
vincristine versus a standard maintenance combination including oral methotrexate given during
two interim maintenance phases.[8][Level of evidence: 1iiDi]
A second delayed intensification phase provided no benefit in patients who were rapid early
responders (M1 or M2 marrow by day 14 of induction).
Escalating IV methotrexate during the interim maintenance phases, compared with oral
methotrexate during these phases, produced a significant improvement in event-free
survival (EFS), which was because of a decreased incidence of isolated extramedullary
relapses, particularly those involving the CNS.
3. In a randomized study conducted in the United Kingdom, children and young adults with ALL who
lacked high-risk features (including adverse cytogenetics, and/or M3 marrow morphology at day 8
or day 15 of induction) were risk-stratified based on minimal residual disease (MRD) level at the
end of induction (week 4) and at week 11 of therapy. Patients with undetectable MRD at week 4 (or
with low MRD at week 4 and undetectable by week 11) were considered low-risk, and were eligible
to be randomly assigned to therapy with either one or two delayed intensification phases.[18][Level
of evidence: 1iiDi]
There was no significant difference in EFS between patients who received one and those who
received two delayed intensification phases.
There was no significant difference in treatment-related deaths between the two arms;
however, the second delayed intensification phase was associated with grade 3 or 4 toxic
events in 17% of the 261 patients randomly assigned to that arm, and one patient
experienced a treatment-related death during that phase.
High-risk ALL
In high-risk patients, a number of different approaches have been used with comparable efficacy.[11,19];
[17][Level of evidence: 2Di] Treatment for high-risk patients generally is more intensive than that for
standard-risk patients and typically includes higher cumulative doses of multiple agents, including
anthracyclines and/or alkylating agents. Higher doses of these agents increase the risk of both short-term
and long-term toxicities, and many clinical trials have focused on reducing the side effects of these
intensified regimens.
Evidence (intensification for high-risk ALL):
1. The former CCG developed an augmented BFM treatment regimen that included a second interim
maintenance and delayed intensification phase. This regimen featured repeated courses of
escalating-dose IV methotrexate (without leucovorin rescue) given with vincristine and L-
asparaginase during interim maintenance and additional vincristine and L-asparaginase pulses
during initial consolidation and delayed intensification. In the CCG-1882 trial, National Cancer
Institute (NCI) high-risk patients with slow early response (M3 marrow on day 7 of induction) were
randomly assigned to receive either standard- or augmented-BFM therapy.[20]
The augmented therapy regimen in the CCG-1882 trial produced a significantly better EFS
than did standard CCG modified BFM therapy.
There was a significantly higher incidence of osteonecrosis in patients older than 10 years
who received the augmented therapy (which included two 21-day postinduction
dexamethasone courses), compared with those who were treated on the standard arm (one
21-day postinduction dexamethasone course).[21]
2. In an Italian study, investigators showed that two applications of delayed intensification therapy
(protocol II) significantly improved outcome for patients with a poor response to a prednisone
prophase.[22]
3. The CCG-1961 study used a 2 2 factorial design to compare both standard- versus augmented-
intensity therapies and therapies of standard duration (one interim maintenance and delayed
intensification phase) versus increased duration (two interim maintenance and delayed
intensification phases) among NCI high-risk patients with a rapid early response. This trial also
tested whether continuous versus alternate-week dexamethasone during delayed intensification
phases affected rates of osteonecrosis.
Augmented therapy was associated with an improvement in EFS; there was no EFS benefit
associated with the administration of the second interim maintenance and delayed
intensification phases.[23][Level of evidence: 1iiA]
The cumulative incidence of osteonecrosis of bone at 5 years was 9.9% for patients aged 10
to 15 years and 20.0% for patients aged 16 to 21 years, compared with 1.0% for patients aged
1 to 9 years (P = .0001). For patients aged 10 to 21 years, alternate-week dosing of
dexamethasone during delayed intensification phases was associated with a significantly
lower cumulative incidence of osteonecrosis, compared with continuous dosing (8.7% vs.
17.0%, P = .0005).[24][Level of evidence: 1iiC]
4. The use of the cardioprotectant agent dexrazoxane has been shown to prevent cardiac toxic effects
without adversely impacting EFS in high-risk ALL patients. In a DFCI ALL Consortium trial,
children with high-risk ALL were randomly assigned to receive doxorubicin alone (30 mg/m2 /dose
to a cumulative dose of 300 mg/m2 ) or the same dose of doxorubicin with dexrazoxane during the
induction and intensification phases of multiagent chemotherapy.[25,26]
The use of the cardioprotectant dexrazoxane before doxorubicin resulted in better left
ventricular fractional shortening and improved end-systolic dimension Z-scores without any
adverse effect on EFS or increase in second malignancy risk, compared with the use of
doxorubicin alone 5 years posttreatment.
A greater long-term protective effect was noted in girls than in boys.
The Pediatric Oncology Group (POG)-9404 trial also demonstrated no difference in EFS
between patients with T-cell ALL who were treated with dexrazoxane and patients who did
not receive dexrazoxane.[27]
Very high-risk ALL
Approximately 10% to 20% of patients with ALL are classified as very high risk, including the following:
[17,28]
Infants.
Patients with adverse cytogenetic abnormalities, including t(9;22), MLL gene rearrangements, and
low hypodiploidy (<44 chromosomes).
Patients who achieve complete remission but have a slow early response to initial therapy,
including those with a high absolute blast count after a 7-day steroid prophase, and patients with
high minimal residual disease (MRD) levels at the end of induction (week 4) or later time points
(e.g., week 12).
Patients who have morphologically persistent disease after the first 4 weeks of therapy (induction
failure), even if they later achieve complete remission.
COG also considers patients who are aged 13 years or older to be very high risk, although this age criterion
is not utilized by other groups.
Patients with very high-risk features have been treated with multiple cycles of intensive chemotherapy
during the consolidation phase (usually in addition to the typical BFM-backbone intensification phases).
These additional cycles often include agents not typically used in frontline ALL regimens for standard-
risk and high-risk patients, such as high-dose cytarabine, ifosfamide, and etoposide.[17] However, even
with this intensified approach, reported long-term EFS rates range from 30% to 50% for this patient
subset.[17,29]
On some clinical trials, very high-risk patients have also been considered candidates for allogeneic
hematopoietic stem cell transplantation (HSCT) in first remission, [29-31] although it is not clear whether
outcomes are better with transplantation.
Evidence (allogeneic HSCT in first remission for very high-risk patients):
1. In a European cooperative group study, very high-risk patients (defined as one of the following:
morphologically persistent disease after a four-drug induction, t(9;22) or t(4;11), or poor response
to prednisone prophase in patients with either T-cell phenotype or presenting white blood cells
[WBC] >100,000/L) were assigned to receive either an allogeneic HSCT in first remission (based
on the availability of a human lymphocyte antigenmatched related donor) or intensive
chemotherapy.[29]
Using an intent-to-treat analysis, patients assigned to allogeneic HSCT (on the basis of donor
availability) had a superior 5-year disease-free survival (DFS) compared with patients
assigned to intensive chemotherapy (57% 7% for transplant versus 41% 3% for
chemotherapy, P = .02)
There was no significant difference in overall survival (OS) (56% 6% for transplant versus
50% 3% for chemotherapy, P = .12).
For patients with T- cell ALL and a poor response to prednisone prophase, both DFS and OS
rates were significantly better with allogeneic HSCT.[30]
2. In another study of very high-risk patients that included children with extremely high presenting
leukocyte counts and those with adverse cytogenetic abnormalities and/or initial induction failure
(M2 marrow [between 5% and 25% blasts]), allogeneic HSCT in first remission was not associated
with either a DFS or OS advantage.[31]
3. In a large retrospective series of patients with initial induction failure, the 10-year OS for patients
with persistent leukemia was 32%.[32]
A trend for superior outcome with allogeneic HSCT, compared with chemotherapy alone,
was observed in patients with T-cell phenotype (any age) and with B-precursor ALL who were
older than 6 years.
Patients with B-precursor ALL who were aged 1 to 5 years at diagnosis and did not have any
adverse cytogenetic abnormalities (MLL translocation, BCR-ABL) had a relatively favorable
prognosis, without any advantage in outcome with the utilization of HSCT compared with
chemotherapy alone.
4. In a Dutch and Australian trial of 111 children with high-risk features or high MRD, patients
received three novel intensive chemotherapy agents followed by allogeneic transplantation. Thirty
of these patients were high risk by MRD and had a 5-year EFS of 64%.[33]
Maintenance therapy
Backbone of maintenance therapy
The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly
oral or parenteral methotrexate. Clinical trials generally call for the administration of oral
mercaptopurine in the evening, which is supported by evidence that this practice may improve EFS.[34]
On many protocols, intrathecal chemotherapy for CNS sanctuary therapy is continued during
maintenance therapy. It is imperative to carefully monitor children on maintenance therapy for both
drug-related toxicity and for compliance with the oral chemotherapy agents used during maintenance
therapy.[35] Nonadherence to treatment with 6-mercaptopurine (6-MP) in the maintenance phase is
associated with a significant increase in the risk of relapse.[35]
Treating physicians must also recognize that some patients may develop severe hematopoietic toxicity
when receiving conventional dosages of mercaptopurine because of an inherited deficiency (homozygous
mutant) of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.[36,37] These
patients are able to tolerate mercaptopurine only if dosages much lower than those conventionally used
are administered.[36,37] Patients who are heterozygous for this mutant enzyme gene generally tolerate
mercaptopurine without serious toxicity, but they do require more frequent dose reductions for
hematopoietic toxicity than do patients who are homozygous for the normal allele.[36]
Evidence (maintenance therapy):
1. In a meta-analysis of randomized trials that compared thiopurines, 6-thioguanine (6-TG) did not
improve the overall EFS, although particular subgroups may benefit from its use.[38] The use of
continuous 6-TG instead of 6-MP during the maintenance phase is associated with an increased risk
of hepatic complications, including veno-occlusive disease and portal hypertension.[39-43]

Because of the increased toxicity of 6-TG, 6-MP remains the standard drug of choice.
2. Another approach is an intensified maintenance phase that consists of rotating pairs of agents,
including cyclophosphamide and epipodophyllotoxins, along with more standard maintenance
agents.[4]
The intensified maintenance with rotating pairs of agents has been associated with more
episodes of febrile neutropenia [44] and a higher risk of secondary acute myelogenous
leukemia,[45] especially when epipodophyllotoxins are included.[44]
SJCRH has modified the agents used in the rotating pair schedule during the maintenance
phase. On the Total XV study, standard-risk and high-risk patients received three rotating
pairs (mercaptopurine plus methotrexate, cyclophosphamide plus cytarabine, and
dexamethasone plus vincristine) throughout this treatment phase; low-risk patients received
more standard maintenance (without cyclophosphamide and cytarabine).[46]
3. A randomized study from Argentina demonstrated no benefit from this intensified approach
compared with a more standard maintenance regimen for patients who receive induction and
consolidation phases based on a BFM backbone.[44]
Vincristine/corticosteroid pulses
Pulses of vincristine and corticosteroid are often added to the standard maintenance backbone, although
the benefit of these pulses within the context of intensive, multiagent regimens remains controversial.
Evidence (vincristine/corticosteroid pulses):
1. A CCG randomized trial conducted in the 1980s demonstrated improved outcome in patients
receiving monthly vincristine/prednisone pulses.[47] A meta-analysis combining data from six
clinical trials from the same treatment era showed an EFS advantage for vincristine/prednisone
pulses.[48,49]
2. A systematic review of the impact of vincristine plus steroid pulses from more recent clinical trials
raised the question of whether such pulses are of value in current ALL treatment, which includes
more intensive early therapy.[49]
3. In a multicenter randomized trial in children with intermediate-risk ALL being treated on a BFM
regimen, there was no benefit associated with the addition of six pulses of
vincristine/dexamethasone during the continuation phase, although the pulses were administered
less frequently than in other trials in which a benefit had been demonstrated.[50]
4. A small multicenter trial of average-risk patients demonstrated superior EFS in patients receiving
vincristine plus corticosteroid pulses. In this study, there was no difference in outcome based on
type of steroid (prednisone vs. dexamethasone).[51][Level of evidence: 1iiA]
For regimens that include vincristine/steroid pulses, a number of studies have addressed which steroid
(dexamethasone or prednisone) should be used. From these studies, it appears that dexamethasone is
associated with superior EFS, but also may lead to a greater frequency of steroid-associated
complications, including bone toxicity and infections, especially in older children and adolescents.
Dexamethasone has not been associated with an increased frequency of these complications in younger
patients.[13,52-55]
Evidence (dexamethasone vs. prednisone):
1. In a CCG study, dexamethasone was compared with prednisone for children aged 1 to younger than
10 years with lower-risk ALL.[13,52]
Patients randomly assigned to receive dexamethasone had significantly fewer CNS relapses
and a significantly better EFS rate.
2. In a Medical Research Council trial, dexamethasone was compared with prednisolone during
induction and maintenance therapies in both standard-risk and high-risk patients.[53]
The EFS and incidence of both CNS and non-CNS relapses improved with the use of
dexamethasone.
Dexamethasone was associated with an increased risk of steroid-associated toxicities,

including behavioral problems, myopathy, and osteopenia.
3. In a DFCI ALL Consortium trial, patients were randomly assigned to receive either dexamethasone
or prednisone during all postinduction treatment phases.[55]
Dexamethasone was associated with a superior EFS, but also with a higher frequency of
infections (primarily episodes of bacteremia) and, in patients aged 10 years or older, an
increased incidence of osteonecrosis and fracture.
The benefit of using dexamethasone in children aged 10 to 18 years requires further investigation because
of the increased risk of steroid-induced osteonecrosis in this age group.[21,54]
Duration of maintenance therapy
Maintenance chemotherapy generally continues until 2 to 3 years of continuous CR. On some studies,
boys are treated longer than girls;[13] on others, there is no difference in the duration of treatment based
on gender.[11,17] It is not clear whether longer duration of maintenance therapy reduces relapse in boys,
especially in the context of current therapies.[17][Level of evidence: 2Di] Extending the duration of
maintenance therapy beyond 3 years does not improve outcome.[48]
Adherence to maintenance therapy
Nonadherence to treatment with 6-MP in maintenance is associated with a significant increase in the risk
of relapse.[35]
Evidence (adherence to treatment):
1. The COG studied the impact of non-adherence to 6-MP during maintenance in 327 children and
adolescents of different ethnic backgrounds.[35]
Adherence declined from 95% to 90% over the 6-month observation period.
Adherence was significantly lower among Hispanics, patients older than 12 years, and
patients from single-mother households.
Lower adherence to 6-MP was associated with a significantly higher risk of relapse. After
adjusting for other prognostic factors (including NCI risk group and chromosomal
abnormalities), a progressive increase in relapse was observed with decreasing adherence.
T reatment options under clinical evaluation
Risk-based treatment assignment is a key therapeutic strategy utilized for children with ALL, and
protocols are designed for specific patient populations that have varying degrees of risk of treatment
failure. The Risk-based Treatment Assignment section of this summary describes the clinical and
laboratory features used for the initial stratification of children with ALL into risk-based treatment
groups.
Ongoing clinical trials include the following:
COG studies for B-precursor ALL
Standard-risk ALL
1. COG-AALL0932 (Risk-Adapted Chemotherapy in Younger Patients With Newly Diagnosed
Standard-Risk ALL):
This trial subdivides standard-risk patients into two groups: low risk and average risk. Low risk is
defined as the presence of all of the following: NCI-standard risk age/WBC, favorable genetics (e.g.,
double trisomies or ETV6-RUNX1), CNS1 at presentation, and low MRD (<0.01% by flow
cytometry) at day 8 (peripheral blood) and day 29 (marrow). Average risk includes other NCI
standard-risk patients excluding those with high day 29 MRD morphologic induction failure or
other unfavorable presenting features (e.g., CNS3, iAMP21, low hypodiploidy, MLL translocations,
and BCR-ABL).
All patients will receive a three-drug induction (dexamethasone, vincristine, and IV PEG-L-
asparaginase) with intrathecal chemotherapy. For postinduction therapy, low-risk patients will be
randomly assigned to receive one of the following:
A regimen based on POG-9904, including six courses of intermediate-dose methotrexate (1

g/m2 ) but without any alkylating agents or anthracyclines.
A modified BFM backbone including two interim maintenance phases with escalating doses
of IV methotrexate (no leucovorin) and one delayed intensification phase.
The objective is not to prove superiority of either regimen, but rather, to determine whether
excellent outcomes (at least 95% 5-year DFS) can be achieved.
All average-risk patients will receive a modified BFM-backbone as postinduction treatment. For
these patients, the study is comparing, in a randomized fashion, two doses of weekly oral
methotrexate during the maintenance phase (20 mg/m2 and 40 mg/m2 ) to determine whether the
higher dose favorably impacts DFS. Average-risk patients are also eligible to participate in a
randomized comparison of two schedules of vincristine/dexamethasone pulses during maintenance
(delivered every 4 weeks or every 12 weeks). The objective of this randomization is to determine
whether vincristine/dexamethasone pulses can be delivered less frequently without adversely
impacting outcome.
High-risk ALL
1. COG-AALL1131 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed
High-Risk ALL):
This protocol is open to patients aged 30 years or younger. Patients treated on this trial are
classified as either high risk or very high risk. The presence of any of the following is sufficient to
classify a patient as very high risk:
Age 13 years or older.
CNS3 at diagnosis.
M3 marrow at day 29.
Unfavorable genetics (e.g., iAMP21, low hypodiploidy, MLL gene rearrangements).
High marrow MRD (>0.01% by flow cytometry) at day 29 (with the exception of NCI
standard-risk patients with favorable genetics).
The high-risk group includes patients with NCI high-risk ALL who lack very high-risk features, and
two groups of NCI standard-risk patients who otherwise lack very high-risk features: (1) those
without favorable genetics (no ETV6-RUNX1 or double trisomies 4 and 10), and with day 8
peripheral blood MRD >1%; and (2) those with favorable cytogenetics and with high marrow MRD
at day 29. Patients with BCR-ABL (Philadelphia chromosomepositive) are treated on a separate
clinical trial.
Patients on this trial will receive a four-drug induction (vincristine, corticosteroid, daunorubicin,
and IV PEG-L-asparaginase) with intrathecal chemotherapy. Patients younger than 10 years
receive dexamethasone during induction, and those aged 10 years and older receive prednisone.
Postinduction therapy consists of a modified BFM backbone, including an interim maintenance
phase with high-dose methotrexate and one delayed intensification phase. Very high-risk patients
receive a second interim maintenance phase before beginning more standard maintenance. Only
patients with CNS3 status at diagnosis receive cranial radiation. Those with M3 marrow at day 29
or low hypodiploidy are eligible for allogeneic HSCT in first remission.
For high-risk patients, the study will compare, in a randomized fashion, triple intrathecal
chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate to
determine whether triple intrathecal chemotherapy reduces CNS relapse rates and improves EFS.
For very high-risk patients, the study will test, in a randomized fashion, whether intensified
consolidation phases (including either cyclophosphamide/etoposide or
clofarabine/cyclophosphamide/etoposide) improves 4-year DFS compared with the standard
consolidation phase.
Other studies
1. T otal XVI study (T OT XVI) (Total Therapy Study XVI for Newly Diagnosed Patients With
ALL): A study at SJCRH is randomly assigning patients to receive either standard-dose (2,500
u/m2 ) or high-dose (3,500 u/m2 ) PEG-L-asparaginase during postremission therapy.
2. DFCI-11-001 (NCT 01574274) (SC-PEG Asparaginase versus Oncaspar in Pediatric ALL and
Lymphoblastic Lymphoma): A DFCI ALL Consortium protocol is comparing the pharmacokinetics
and toxicity of two forms of IV PEG-L-asparaginase (pegaspargase [Oncaspar] and calaspargase
pegol [SC-PEG]). Patients will be randomly assigned to receive a single dose of one of these
preparations during multiagent induction, and then either pegaspargase every 2 weeks (15 doses
total) or calaspargase pegol every 3 weeks (10 doses total) during the 30-week consolidation phase.
This protocol is also examining the following:
Whether an intensified consolidation including high-dose cytarabine and etoposide improves

the outcome for very high-risk patients (patients with high MRD at the end of remission
induction, MLL translocations, or hypodiploidy [<44 chromosomes]).
Whether antibiotic prophylaxis (with fluoroquinolones) reduces rates of bacteremia and

other serious bacterial infections during the remission induction phase.
childhood acute lymphoblastic leukemia in remission. The list of clinical trials can be further narrowed by
References

A bstract]
5. Veerman AJ, Hhlen K, Kamps WA, et al.: High cure rate with a moderately intensive treatment
regimen in non-high-risk childhood acute lymphoblastic leukemia. Results of protocol ALL VI from
the Dutch Childhood Leukemia Study Group. J Clin Oncol 14 (3): 911-8, 1996. [PUBMED A bstract]
6. Chauvenet AR, Martin PL, Devidas M, et al.: Antimetabolite therapy for lesser-risk B-lineage acute
lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201.
7. Gustafsson G, Kreuger A, Clausen N, et al.: Intensified treatment of acute childhood lymphoblastic

leukaemia has improved prognosis, especially in non-high-risk patients: the Nordic experience of
2648 patients diagnosed between 1981 and 1996. Nordic Society of Paediatric Haematology and
Oncology (NOPHO) Acta Paediatr 87 (11): 1151-61, 1998. [PUBMED A bstract]
9. Mahoney DH Jr, Shuster JJ, Nitschke R, et al.: Intensification with intermediate-dose intravenous
methotrexate is effective therapy for children with lower-risk B-precursor acute lymphoblastic
leukemia: A Pediatric Oncology Group study. J Clin Oncol 18 (6): 1285-94, 2000. [PUBMED A bstract]
12. Pession A, Valsecchi MG, Masera G, et al.: Long-term results of a randomized trial on extended use
of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia. J Clin Oncol
23 (28): 7161-7, 2005. [PUBMED A bstract]
14. Riehm H, Gadner H, Henze G, et al.: Results and significance of six randomized trials in four
consecutive ALL-BFM studies. Hamatol Bluttransfus 33: 439-50, 1990. [PUBMED A bstract]
15. Hutchinson RJ, Gaynon PS, Sather H, et al.: Intensification of therapy for children with lower-risk
acute lymphoblastic leukemia: long-term follow-up of patients treated on Children's Cancer Group
Trial 1881. J Clin Oncol 21 (9): 1790-7, 2003. [PUBMED A bstract]
A bstract]

18. Vora A, Goulden N, Wade R, et al.: Treatment reduction for children and young adults with low-
risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a
randomised controlled trial. Lancet Oncol 14 (3): 199-209, 2013. [PUBMED A bstract]
19. Pui CH, Mahmoud HH, Rivera GK, et al.: Early intensification of intrathecal chemotherapy
virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia.
20. Nachman JB, Sather HN, Sensel MG, et al.: Augmented post-induction therapy for children with
high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 338
(23): 1663-71, 1998. [PUBMED A bstract]
21. Mattano LA Jr, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute
lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 18
(18): 3262-72, 2000. [PUBMED A bstract]
22. Aric M, Valsecchi MG, Conter V, et al.: Improved outcome in high-risk childhood acute
lymphoblastic leukemia defined by prednisone-poor response treated with double Berlin-
Frankfurt-Muenster protocol II. Blood 100 (2): 420-6, 2002. [PUBMED A bstract]
23. Seibel NL, Steinherz PG, Sather HN, et al.: Early postinduction intensification therapy improves
survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from
the Children's Oncology Group. Blood 111 (5): 2548-55, 2008. [PUBMED A bstract]
24. Mattano LA Jr, Devidas M, Nachman JB, et al.: Effect of alternate-week versus continuous
dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute
lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial. Lancet Oncol 13 (9):
25. Lipshultz SE, Scully RE, Lipsitz SR, et al.: Assessment of dexrazoxane as a cardioprotectant in
doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of
a prospective, randomised, multicentre trial. Lancet Oncol 11 (10): 950-61, 2010. [PUBMED A bstract]
26. Barry EV, Vrooman LM, Dahlberg SE, et al.: Absence of secondary malignant neoplasms in children
with high-risk acute lymphoblastic leukemia treated with dexrazoxane. J Clin Oncol 26 (7): 1106-
27. Asselin B, Devidas M, Zhou T, et al.: Cardioprotection and safety of dexrazoxane (DRZ) in children
treated for newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or advanced stage
lymphoblastic leukemia (T-LL). [Abstract] J Clin Oncol 30 (Suppl 15): A-9504, 2012.
28. Schultz KR, Pullen DJ, Sather HN, et al.: Risk- and response-based classification of childhood B-
precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the
Pediatric Oncology Group (POG) and Children's Cancer Group (CCG). Blood 109 (3): 926-35,
30. Schrauder A, Reiter A, Gadner H, et al.: Superiority of allogeneic hematopoietic stem-cell

transplantation compared with chemotherapy alone in high-risk childhood T-cell acute
lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol 24 (36): 5742-9, 2006.
[PUBMED A bstract]
31. Ribera JM, Ortega JJ, Oriol A, et al.: Comparison of intensive chemotherapy, allogeneic, or
autologous stem-cell transplantation as postremission treatment for children with very high risk
acute lymphoblastic leukemia: PETHEMA ALL-93 Trial. J Clin Oncol 25 (1): 16-24, 2007. [PUBMED
A bstract]
33. Marshall GM, Dalla Pozza L, Sutton R, et al.: High-risk childhood acute lymphoblastic leukemia in
first remission treated with novel intensive chemotherapy and allogeneic transplantation.
34. Schmiegelow K, Glomstein A, Kristinsson J, et al.: Impact of morning versus evening schedule for
oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic
leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO). J Pediatr Hematol
Oncol 19 (2): 102-9, 1997 Mar-Apr. [PUBMED A bstract]
36. Relling MV, Hancock ML, Rivera GK, et al.: Mercaptopurine therapy intolerance and
heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91 (23): 2001-
37. Andersen JB, Szumlanski C, Weinshilboum RM, et al.: Pharmacokinetics, dose adjustments, and 6-
mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase
deficiency. Acta Paediatr 87 (1): 108-11, 1998. [PUBMED A bstract]
38. Escherich G, Richards S, Stork LC, et al.: Meta-analysis of randomised trials comparing thiopurines
in childhood acute lymphoblastic leukaemia. Leukemia 25 (6): 953-9, 2011. [PUBMED A bstract]
39. Broxson EH, Dole M, Wong R, et al.: Portal hypertension develops in a subset of children with
standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance
therapy. Pediatr Blood Cancer 44 (3): 226-31, 2005. [PUBMED A bstract]
40. De Bruyne R, Portmann B, Samyn M, et al.: Chronic liver disease related to 6-thioguanine in
children with acute lymphoblastic leukaemia. J Hepatol 44 (2): 407-10, 2006. [PUBMED A bstract]
41. Vora A, Mitchell CD, Lennard L, et al.: Toxicity and efficacy of 6-thioguanine versus 6-
mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet 368 (9544):
42. Jacobs SS, Stork LC, Bostrom BC, et al.: Substitution of oral and intravenous thioguanine for
mercaptopurine in a treatment regimen for children with standard risk acute lymphoblastic
leukemia: a collaborative Children's Oncology Group/National Cancer Institute pilot trial (CCG-
1942). Pediatr Blood Cancer 49 (3): 250-5, 2007. [PUBMED A bstract]
43. Stork LC, Matloub Y, Broxson E, et al.: Oral 6-mercaptopurine versus oral 6-thioguanine and veno-
occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the
Children's Oncology Group CCG-1952 clinical trial. Blood 115 (14): 2740-8, 2010. [PUBMED A bstract]
44. Felice MS, Rossi JG, Gallego MS, et al.: No advantage of a rotational continuation phase in acute
lymphoblastic leukemia in childhood treated with a BFM back-bone therapy. Pediatr Blood Cancer
57 (1): 47-55, 2011. [PUBMED A bstract]
45. Hijiya N, Hudson MM, Lensing S, et al.: Cumulative incidence of secondary neoplasms as a first
event after childhood acute lymphoblastic leukemia. JAMA 297 (11): 1207-15, 2007. [PUBMED
A bstract]
47. Bleyer WA, Sather HN, Nickerson HJ, et al.: Monthly pulses of vincristine and prednisone prevent
bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of
the CCG-161 study by the Childrens Cancer Study Group. J Clin Oncol 9 (6): 1012-21, 1991.
[PUBMED A bstract]
48. Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview
of 42 trials involving 12 000 randomised children. Childhood ALL Collaborative Group. Lancet
347 (9018): 1783-8, 1996. [PUBMED A bstract]
49. Eden TO, Pieters R, Richards S, et al.: Systematic review of the addition of vincristine plus steroid
pulses in maintenance treatment for childhood acute lymphoblastic leukaemia - an individual
patient data meta-analysis involving 5,659 children. Br J Haematol 149 (5): 722-33, 2010. [PUBMED
A bstract]
50. Conter V, Valsecchi MG, Silvestri D, et al.: Pulses of vincristine and dexamethasone in addition to
intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a
multicentre randomised trial. Lancet 369 (9556): 123-31, 2007. [PUBMED A bstract]
51. De Moerloose B, Suciu S, Bertrand Y, et al.: Improved outcome with pulses of vincristine and
corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia
(ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3
trial 58951. Blood 116 (1): 36-44, 2010. [PUBMED A bstract]
54. Strauss AJ, Su JT, Dalton VM, et al.: Bony morbidity in children treated for acute lymphoblastic
leukemia. J Clin Oncol 19 (12): 3066-72, 2001. [PUBMED A bstract]
55. Vrooman LM, Stevenson KE, Supko JG, et al.: Postinduction dexamethasone and individualized
dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with
newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber
Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 31 (9): 1202-10, 2013. [PUBMED
A bstract]
CNS-directed Therapy for Childhood ALL
Approximately 3% of patients have detectable central nervous system (CNS) involvement by

conventional criteria at diagnosis (cerebrospinal fluid [CSF] specimen with 5 white blood cell [WBC]/L
with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is
directed toward the CNS, the majority of children will eventually develop overt CNS leukemia. Therefore,
all children with acute lymphoblastic leukemia (ALL) should receive systemic combination chemotherapy
together with some form of CNS prophylaxis.
Because the CNS is a sanctuary site (i.e., an anatomic space that is poorly penetrated by many of the
systemically administered chemotherapy agents typically used to treat ALL), specific CNS-directed
therapies must be instituted early in treatment to eliminate clinically evident CNS disease at diagnosis and
to prevent CNS relapse in all patients. Historically, survival rates for children with ALL improved
dramatically after CNS-directed therapies were added to treatment regimens.
Standard treatment options for CNS-directed therapy include the following:
1. Intrathecal chemotherapy.
2. CNS-directed systemic chemotherapy.
3. Cranial radiation.
All of these treatment modalities have a role in the treatment and prevention of CNS leukemia. The
combination of intrathecal chemotherapy plus CNS-directed systemic chemotherapy is standard; cranial
radiation is reserved for selective situations.[1]
The type of CNS-therapy that is used is based on a patients risk of CNS-relapse, with higher-risk patients
receiving more intensive treatments. Data suggest that the following groups of patients are at increased
risk of CNS relapse:
Patients with five or more WBC/L and blasts in the CSF (CNS3), obtained at diagnosis.
Patients with blasts in the CSF but fewer than 5 WBC/L (CNS2) may be at increased risk of CNS
relapse,[2] although this risk appears to be nearly fully abrogated if they receive more doses of
intrathecal chemotherapy, especially during the induction phase.[3]
Patients with T-cell ALL, especially those with high presenting peripheral blood leukocyte counts.
Patients who have a traumatic lumbar puncture showing blasts at the time of diagnosis may have an
increased risk of CNS relapse. These patients receive more intensive CNS-directed therapy on
some treatment protocols.[3,4]
CNS-directed treatment regimens for newly diagnosed childhood ALL are presented in Table 2:
Table 2. CNS-Directed Treatment Regimens for Newly Diagnosed Childhood ALL

Enlarge
Di sea se St a t u s St a n da r d T r ea t m en t Opt i on s
St a n da r d-r isk A LL In t r a t h eca l ch em ot h er a py
Met h ot r ex a t e a lon e
Met h ot r ex a t e w it h cy t a r a bin e a n d h y dr ocor t ison e
CNS-dir ect ed sy st em ic ch em ot h er a py
Dex a m et h a son e
L-a spa r a g in a se a
Hig h -dose m et h ot r ex a t e w it h leu cov or in r escu e
Esca la t in g -dose in t r a v en ou s m et h ot r ex a t e (n o leu cov or in r escu e)
Hig h -r isk A LL In t r a t h eca l ch em ot h er a py
Met h ot r ex a t e a lon e
Met h ot r ex a t e w it h cy t a r a bin e a n d h y dr ocor t ison e
CNS-dir ect ed sy st em ic ch em ot h er a py
Dex a m et h a son e
L-a spa r a g in a se a
Hig h -dose m et h ot r ex a t e w it h leu cov or in r escu e
Cr a n ia l r a dia t ion
ALL = acute lym phoblas tic leuk em ia; CNS = central nervous s ys tem ; CNS3 = cerebros pinal fluid w ith five or m ore w hite
blood cells /L, cytos pin pos itive for blas ts , or cranial nerve pals ies .
a The drug its elf is not CNS-penetrant, but leads to cerebros pinal fluid as paragine depletion.
A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurologic
toxic effects and other late effects.
Intrathecal Chemotherapy
All therapeutic regimens for childhood ALL include intrathecal chemotherapy. Intrathecal chemotherapy
is usually started at the beginning of induction, intensified during consolidation and, in many protocols,
continued throughout the maintenance phase.
Intrathecal chemotherapy typically consists of one of the following:[5]
1. Methotrexate alone.
2. Methotrexate with cytarabine and hydrocortisone (triple intrathecal chemotherapy).
Unlike intrathecal cytarabine, intrathecal methotrexate has a significant systemic effect, which may
contribute to prevention of marrow relapse.[6]
CNS-directed Systemic Chemotherapy
In addition to therapy delivered directly to the brain and spinal fluid, systemically administered agents
are also an important component of effective CNS prophylaxis. The following systemically administered
drugs provide some degree of CNS prophylaxis:
Dexamethasone.
L-asparaginase (does not penetrate into CSF itself, but leads to CSF asparagine depletion).
High-dose methotrexate with leucovorin rescue.
Escalating dose intravenous (IV) methotrexate without leucovorin rescue.
Evidence (CNS-directed systemic chemotherapy):
1. In a randomized Children's Cancer Group (CCG) study of standard-risk patients who all received
the same dose and schedule of intrathecal methotrexate without cranial irradiation, oral
dexamethasone was associated with a 50% decrease in the rate of CNS relapse compared with oral
prednisone.[7]
2. In another standard-risk ALL trial (COG-1991), escalating dose IV methotrexate without rescue
significantly reduced the CNS relapse rate compared with standard, low-dose, oral methotrexate
given during each of two interim maintenance phases.[8]
3. In a randomized clinical trial conducted by the former Pediatric Oncology Group, T-cell ALL
patients who received high-dose methotrexate experienced a significantly lower CNS relapse rate
than patients who did not receive high-dose methotrexate.[9]
Cranial Radiation
The proportion of patients receiving cranial radiation has decreased significantly over time. At present,
most newly diagnosed children with ALL are treated without cranial radiation. Many groups administer
cranial radiation only to those patients considered to be at highest risk of subsequent CNS relapse, such as
those with documented CNS leukemia at diagnosis (as defined above) (>5 WBC/L with blasts; CNS3)
and/or T-cell phenotype with high presenting WBC count.[10] In patients who do receive cranial
radiation, the dose has been significantly reduced.
Ongoing trials seek to determine whether radiation can be eliminated from the treatment of all children
with ALL without compromising survival or leading to increased rate of toxicities from upfront and
salvage therapies.[11,12] A meta-analysis of randomized trials of CNS-directed therapy has confirmed
that radiation therapy can be replaced by intrathecal chemotherapy in most patients with ALL. Additional
systemic therapy may be required depending on the agents and intensity used.[1][Level of evidence: 1iDi]
CNS Therapy for Standard-risk Patients
Intrathecal chemotherapy without cranial radiation, given in the context of appropriate systemic
chemotherapy, results in CNS relapse rates of less than 5% for children with standard-risk ALL.[11-16]
The use of cranial radiation does not appear to be a necessary component of CNS-directed therapy for
these patients.[17,18]
Evidence (triple intrathecal chemotherapy vs. intrathecal methotrexate):
1. The CCG-1952 study for National Cancer Institute (NCI) standard-risk patients compared the
relative efficacy and toxicity of triple intrathecal chemotherapy (methotrexate, hydrocortisone,
and cytarabine) with methotrexate as the sole intrathecal agent in nonirradiated patients.[19]
a. There was no significant difference in either CNS or non-CNS toxicities.
b. Although triple intrathecal chemotherapy was associated with a lower rate of isolated CNS
relapse (3.4% 1.0% compared with 5.9% 1.2% for intrathecal methotrexate; P = .004),
there was no difference in event-free survival (EFS).
This effect was especially notable in patients with CNS2 status at diagnosis
(lymphoblasts seen in CSF cytospin, but with <5 WBC/high-power field [hpf] on CSF
cell count); the isolated CNS relapse rate was 7.7% 5.3% for CNS2 patients who
received triple intrathecal chemotherapy compared with 23.0% 9.5% for those who
received intrathecal methotrexate alone (P = .04).
There were more bone marrow relapses in the group that received the triple
intrathecal chemotherapy, leading to a worse overall survival (OS) (90.3% 1.5%)
compared with the intrathecal methotrexate group (94.4% 1.1%; P = .01).
When the analysis was restricted to patients with precursor B-cell ALL and rapid early
response (M1 marrow on day 14), there was no difference between triple and single
intrathecal chemotherapy in terms of rates of CNS relapse rate, OS, or EFS.
The findings of this trial need to be interpreted within the context of other therapy
administered to patients. Dexamethasone, which has been associated with lower CNS
relapse rates and improved EFS in standard-risk patients in other trials,[7,20] was not
used in CCG-1952 (prednisone was the only steroid administered to patients).[21] It is
not clear whether the results of the CCG-1952 trial are generalizable to protocols that
include the use of dexamethasone and/or other CNS-directed systemic therapies.
c. In a follow-up study of neurocognitive functioning in the two groups, there were no clinically
significant differences.[22][Level of evidence: 1iiC]
CNS Therapy for High-risk Patients
Controversy exists as to which high-risk patients should be treated with cranial radiation. Depending on
the protocol, up to 20% of children with ALL receive cranial radiation as part of their CNS-directed
therapy, even if they present without CNS involvement at diagnosis. Patients receiving cranial radiation
on many treatment regimens include the following:[10]
Patients with T-cell phenotype and high initial WBC count.
Patients with high-risk precursor B-cell ALL (e.g., extremely high presenting leukocyte counts
and/or adverse cytogenetic abnormalities and/or CNS3 disease).
Both the proportion of patients receiving radiation and the dose of radiation administered have decreased
over the last 2 decades.
Evidence (cranial radiation):
1. In a trial conducted between 1990 and 1995, the Berlin-Frankfurt-Mnster (BFM) group
demonstrated that a reduced dose of prophylactic radiation (12 Gy instead of 18 Gy) provided
effective CNS prophylaxis in high-risk patients.[23]
2. In the follow-up trial conducted by the BFM group between 1995 and 2000 (BFM-95), cranial
radiation was administered to approximately 20% of patients (compared with 70% on the previous
trial), including patients with T-cell phenotype, a slow early response (as measured by peripheral
blood blast count after a 1-week steroid prophase), and/or adverse cytogenetic abnormalities.[16]
While the rate of isolated CNS relapses was higher in the nonirradiated higher-risk patients
compared with historic (irradiated) cohorts, their overall EFS rate was not significantly
different.
3. Several groups, including the St. Jude Children's Research Hospital (SJCRH), the Dutch Childhood
Oncology Group (DCOG), and the European Organization for Research and Treatment of Cancer
(EORTC), have published results of trials that omitted cranial radiation for all patients, including
high-risk subsets.[11,12,24] Most of these trials have included at least four doses of high-dose
methotrexate during postinduction consolidation and an increased frequency of intrathecal
chemotherapy. The SJCRH and DCOG studies also included frequent vincristine/dexamethasone
pulses and intensified dosing of L-asparaginase,[11,12] while the EORTC trials included additional
high-dose methotrexate and multiple doses of high-dose cytarabine during postinduction treatment
phases for CNS3 (CSF with 5 WBC/L and cytospin positive for blasts) patients.[24]
The 5-year cumulative incidence of isolated CNS relapse on those trials was between 2% and
4%, although some patient subsets had a significantly higher rate of CNS relapse. On the
SJCRH study, clinical features associated with a significantly higher risk of isolated CNS
relapse included T-cell phenotype, the t(1;19) translocation, or the presence of blasts in the
CSF at diagnosis.[11]
The overall EFS for the SJCRH study was 85.6% and 81% for the DCOG study, both in line
with outcomes achieved by contemporaneously conducted clinical trials on which some
patients received prophylactic radiation, but was lower on the EORTC trial (8-year EFS,
69.6%).[24]
Of note, on the SJCRH study, 33 of 498 (6.6%) patients in first remission with high-risk
features (including 26 with high minimal residual disease, six with Philadelphia chromosome-
positive ALL, and one with near haploidy) received an allogeneic hematopoietic stem cell
transplant , which included total-body irradiation.[11]
CNS Therapy for Patients With CNS Involvement (CNS3 Disease) at Diagnosis
Therapy for ALL patients with clinically evident CNS disease (5 WBC/hpf with blasts on cytospin; CNS3)
at diagnosis typically includes intrathecal chemotherapy and cranial radiation (usual dose is 18 Gy).
[16,18] Spinal radiation is no longer used.
Evidence (cranial radiation):
1. SJCRH, DCOG, and the EORTC have published results of trials that omitted cranial radiation for all
patients, including high-risk subsets.[11,24] These trials have included at least four doses of high-
dose methotrexate during postinduction consolidation and an increased frequency of intrathecal
chemotherapy. The SJCRH study also included higher cumulative doses of anthracycline than on
Childrens Oncology Group (COG) trials, and frequent vincristine/dexamethasone pulses and
intensified dosing of L-asparaginase,[11] while the EORTC trials included additional high-dose
methotrexate and multiple doses of high-dose cytarabine, during postinduction treatment phases
for CNS3 (CSF with 5 WBC/L and cytospin positive for blasts) patients.[24]
On the SJCRH Total XV (TOTXV) study, patients with CNS3 status (N = 9) were treated
without cranial radiation (observed 5-year EFS, 43% 23%).[11] On this study, CNS
leukemia at diagnosis (defined as CNS3 status or traumatic lumbar puncture with blasts) was
an independent predictor of inferior EFS.
On the DCOG-9 trial, the 5-year EFS of CNS3 patients (n = 21) treated without cranial
radiation was 67% 10%.[12]
On the EORTC trial, the 8-year EFS of CNS3 patients (n = 49) treated without cranial
radiation was 68%. The cumulative incidence of isolated CNS relapse for those patients was
9.4%.[24][Level of evidence: 2A]
Larger studies will be necessary to fully elucidate the safety of omitting cranial radiation in CNS3 patients.
Presymptomatic CNS Therapy Options Under Clinical Evaluation
Treatment options under clinical evaluation include the following:
1. COG-AALL0434 (NCT 00408005) (Combination Chemotherapy in Treating Young Patients

With Newly Diagnosed T-Cell ALL or T-cell Lymphoblastic Lymphoma): In the COG protocol
(COG-AALL0434) for patients with T-cell ALL, low-risk T-cell patients (those with NCI standard-
risk features, no evidence of CNS disease, and a rapid response to induction therapy) are treated
without cranial radiation, and intermediate-risk and high-risk T-cell patients receive 12 Gy (instead
of 18 Gy) cranial radiation. Patients with CNS3 disease at diagnosis continue to receive 18 Gy
cranial radiation. All patients are randomly assigned to receive either high-dose methotrexate (5
g/m2 over 24 hours) with leucovorin rescue or escalating-dose methotrexate without leucovorin
rescue during the initial interim maintenance phase of therapy. Intermediate-risk and high-risk
patients are also randomly assigned to receive or not receive nelarabine, an antipurine with
selective activity in T-lymphoblasts.

High-Risk ALL): The COG-AALL1131 protocol for patients with high-risk B-precursor ALL includes
a randomized comparison of triple intrathecal chemotherapy (methotrexate, cytarabine, and
hydrocortisone) with intrathecal methotrexate, with the objective of determining whether triple
intrathecal chemotherapy reduces CNS-relapse rates and improves overall EFS. Only patients with
CNS3 status at diagnosis will receive cranial radiation (18 Gy).
3. SJCRH T otal XVI (T OT XVI) (Total Therapy Study XVI for Newly Diagnosed Patients With
ALL): Patients receive both intrathecal chemotherapy and high-dose methotrexate without
radiation therapy. Certain patients with high-risk features, including those with a t(1;19)
translocation, receive intensified intrathecal therapy.
Toxicity of CNS-directed Therapy
Toxic effects of CNS-directed therapy for childhood ALL can be divided into the following two broad
groups:
1. Acute/subacute toxicities (e.g., seizures, stroke, somnolence syndrome, and ascending paralysis).
2. Late-developing toxicities (e.g., meningiomas and other second neoplasms; leukoencephalopathy;

and a range of neurocognitive, behavioral, and neuroendocrine disturbances).[25-27]
Acute/subacute toxicities
The most common acute side effect associated with intrathecal chemotherapy alone is seizures. Up to 5%
of nonirradiated patients with ALL treated with frequent doses of intrathecal chemotherapy will have at
least one seizure during therapy.[11] Higher rates of seizure were observed with consolidation regimens
that included multiple doses of high-dose methotrexate in addition to intrathecal chemotherapy.[28]
Patients with ALL who develop seizures during the course of treatment and who receive anticonvulsant
therapy should not receive phenobarbital or phenytoin as anticonvulsant treatment, as these drugs may
increase the clearance of some chemotherapeutic drugs and adversely affect treatment outcome.[29]
Gabapentin or valproic acid are alternative anticonvulsants with less enzyme-inducing capabilities.[29]
Late-developing toxicities
In general, patients who receive intrathecal chemotherapy without cranial radiation appear to have less
severe neurocognitive sequelae than irradiated patients, and the deficits that do develop represent
relatively modest declines in a limited number of domains of neuropsychological functioning.[30-33]

This modest decline is primarily seen in young children and girls.[34]
A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple intrathecal
chemotherapy showed no clinically meaningful difference.[22][Level of evidence: 3iiiC]
Controversy exists about whether patients who receive dexamethasone have a higher risk of
neurocognitive disturbances.[35] Long-term neurocognitive testing in 92 children with a history of
standard-risk ALL who had received either dexamethasone or prednisone during treatment did not
demonstrate any meaningful differences in cognitive functioning based on corticosteroid randomization.
[36]
Long-term deleterious effects of cranial radiation, particularly at doses higher than 18 Gy, have been
recognized for years. Children receiving these higher doses of cranial radiation are at significant risk of
neurocognitive and neuroendocrine sequelae.[37-41] At doses of 18 Gy, it does not appear that irradiated
patients have more severe neurocognitive impairments than ALL survivors who were treated without
radiation.[30] On current clinical trials, many patients who receive prophylactic or presymptomatic
cranial radiation are treated with an even lower dose. Longer follow-up is needed to determine whether 12
Gy will be associated with a lower incidence of late effects.
The following groups have been associated with neurocognitive and neuroendocrine sequelae after
cranial radiation:
Young children (i.e., younger than 4 years) are at increased risk of neurocognitive decline and
other sequelae after cranial radiation.[42-44]
Girls may be at a higher risk than boys of radiation-induced neuropsychologic and neuroendocrine
sequelae.[43-45]
Long-term survivors treated with 18 Gy radiation appear to have less severe neurocognitive
sequelae than those who had received higher doses of radiation (2428 Gy) on clinical trials
conducted in the 1970s and 1980s.[46]
Evidence (toxicity of cranial radiation):
1. In a randomized trial, hyperfractionated radiation (at a dose of 18 Gy) did not decrease neurologic
late effects when compared with conventionally fractionated radiation; cognitive function for both
groups was not significantly impaired.[47]
2. In another randomized trial comparing irradiated (at a dose of 18 Gy) and nonirradiated standard-
risk ALL patients, cognitive function for both groups (assessed at a median of 6 years
postdiagnosis) was in the average range, with only subtle differences noted between the groups in
cognitive skills.[30][Level of evidence: 1iiC]
Cranial radiation has also been associated with an increased risk of second neoplasms, many of which are
benign or of low malignant potential, such as meningiomas, although high-grade lesions may occur.
[27,48,49] Leukoencephalopathy has been observed after cranial radiation in children with ALL but
appears to be more common with higher doses than are currently administered.[50] In general, systemic
methotrexate doses greater than 1 g/m2 should not be given after cranial radiation because of the
increased risk of neurologic sequelae, including leukoencephalopathy.
References
1. Richards S, Pui CH, Gayon P, et al.: Systematic review and meta-analysis of randomized trials of
central nervous system directed therapy for childhood acute lymphoblastic leukemia. Pediatr
Blood Cancer 60 (2): 185-95, 2013. [PUBMED A bstract]
2. Mahmoud HH, Rivera GK, Hancock ML, et al.: Low leukocyte counts with blast cells in
cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med
329 (5): 314-9, 1993. [PUBMED A bstract]
3. Brger B, Zimmermann M, Mann G, et al.: Diagnostic cerebrospinal fluid examination in children

with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic
lumbar puncture. J Clin Oncol 21 (2): 184-8, 2003. [PUBMED A bstract]
4. Gajjar A, Harrison PL, Sandlund JT, et al.: Traumatic lumbar puncture at diagnosis adversely
affects outcome in childhood acute lymphoblastic leukemia. Blood 96 (10): 3381-4, 2000. [PUBMED
A bstract]
5. Pullen J, Boyett J, Shuster J, et al.: Extended triple intrathecal chemotherapy trial for prevention
of CNS relapse in good-risk and poor-risk patients with B-progenitor acute lymphoblastic leukemia:
a Pediatric Oncology Group study. J Clin Oncol 11 (5): 839-49, 1993. [PUBMED A bstract]
6. Thyss A, Suciu S, Bertrand Y, et al.: Systemic effect of intrathecal methotrexate during the initial
phase of treatment of childhood acute lymphoblastic leukemia. The European Organization for
Research and Treatment of Cancer Children's Leukemia Cooperative Group. J Clin Oncol 15 (5):
9. Asselin BL, Devidas M, Wang C, et al.: Effectiveness of high-dose methotrexate in T-cell

lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the
Children's Oncology Group (POG 9404). Blood 118 (4): 874-83, 2011. [PUBMED A bstract]
10. Pui CH, Howard SC: Current management and challenges of malignant disease in the CNS in
paediatric leukaemia. Lancet Oncol 9 (3): 257-68, 2008. [PUBMED A bstract]
13. Pui CH, Sandlund JT, Pei D, et al.: Improved outcome for children with acute lymphoblastic
leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 104
(9): 2690-6, 2004. [PUBMED A bstract]
14. Tubergen DG, Gilchrist GS, O'Brien RT, et al.: Prevention of CNS disease in intermediate-risk acute
lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the
importance of systemic therapy: a Childrens Cancer Group report. J Clin Oncol 11 (3): 520-6, 1993.
[PUBMED A bstract]
15. Conter V, Aric M, Valsecchi MG, et al.: Extended intrathecal methotrexate may replace cranial
irradiation for prevention of CNS relapse in children with intermediate-risk acute lymphoblastic
leukemia treated with Berlin-Frankfurt-Mnster-based intensive chemotherapy. The Associazione
Italiana di Ematologia ed Oncologia Pediatrica. J Clin Oncol 13 (10): 2497-502, 1995. [PUBMED
A bstract]

17. Clarke M, Gaynon P, Hann I, et al.: CNS-directed therapy for childhood acute lymphoblastic
leukemia: Childhood ALL Collaborative Group overview of 43 randomized trials. J Clin Oncol 21
(9): 1798-809, 2003. [PUBMED A bstract]
19. Matloub Y, Lindemulder S, Gaynon PS, et al.: Intrathecal triple therapy decreases central nervous
system relapse but fails to improve event-free survival when compared with intrathecal
methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute
lymphoblastic leukemia, reported by the Children's Oncology Group. Blood 108 (4): 1165-73,
21. Vrooman LM, Stevenson KE, Supko JG, et al.: Postinduction dexamethasone and individualized
dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with
newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber
Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 31 (9): 1202-10, 2013. [PUBMED
A bstract]
22. Kadan-Lottick NS, Brouwers P, Breiger D, et al.: Comparison of neurocognitive functioning in

children previously randomly assigned to intrathecal methotrexate compared with triple
intrathecal therapy for the treatment of childhood acute lymphoblastic leukemia. J Clin Oncol 27
(35): 5986-92, 2009. [PUBMED A bstract]
A bstract]
24. Sirvent N, Suciu S, Rialland X, et al.: Prognostic significance of the initial cerebro-spinal fluid (CSF)
involvement of children with acute lymphoblastic leukaemia (ALL) treated without cranial
irradiation: results of European Organization for Research and Treatment of Cancer (EORTC)
Children Leukemia Group study 58881. Eur J Cancer 47 (2): 239-47, 2011. [PUBMED A bstract]
25. Moore IM, Espy KA, Kaufmann P, et al.: Cognitive consequences and central nervous system injury
following treatment for childhood leukemia. Semin Oncol Nurs 16 (4): 279-90; discussion 291-9,
26. Goshen Y, Stark B, Kornreich L, et al.: High incidence of meningioma in cranial irradiated survivors
of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 49 (3): 294-7, 2007. [PUBMED
A bstract]
27. Hijiya N, Hudson MM, Lensing S, et al.: Cumulative incidence of secondary neoplasms as a first
event after childhood acute lymphoblastic leukemia. JAMA 297 (11): 1207-15, 2007. [PUBMED
A bstract]
28. Mahoney DH Jr, Shuster JJ, Nitschke R, et al.: Acute neurotoxicity in children with B-precursor
acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and
intrathecal triple therapy--a Pediatric Oncology Group study. J Clin Oncol 16 (5): 1712-22, 1998.
[PUBMED A bstract]
29. Relling MV, Pui CH, Sandlund JT, et al.: Adverse effect of anticonvulsants on efficacy of
chemotherapy for acute lymphoblastic leukaemia. Lancet 356 (9226): 285-90, 2000. [PUBMED
A bstract]
30. Waber DP, Turek J, Catania L, et al.: Neuropsychological outcomes from a randomized trial of
triple intrathecal chemotherapy compared with 18 Gy cranial radiation as CNS treatment in acute
lymphoblastic leukemia: findings from Dana-Farber Cancer Institute ALL Consortium Protocol 95-
01. J Clin Oncol 25 (31): 4914-21, 2007. [PUBMED A bstract]
31. Jansen NC, Kingma A, Schuitema A, et al.: Neuropsychological outcome in chemotherapy-only-

treated children with acute lymphoblastic leukemia. J Clin Oncol 26 (18): 3025-30, 2008. [PUBMED
A bstract]
32. Espy KA, Moore IM, Kaufmann PM, et al.: Chemotherapeutic CNS prophylaxis and
neuropsychologic change in children with acute lymphoblastic leukemia: a prospective study. J
Pediatr Psychol 26 (1): 1-9, 2001 Jan-Feb. [PUBMED A bstract]
33. Copeland DR, Moore BD 3rd, Francis DJ, et al.: Neuropsychologic effects of chemotherapy on
children with cancer: a longitudinal study. J Clin Oncol 14 (10): 2826-35, 1996. [PUBMED A bstract]
34. von der Weid N, Mosimann I, Hirt A, et al.: Intellectual outcome in children and adolescents with
acute lymphoblastic leukaemia treated with chemotherapy alone: age- and sex-related differences.
Eur J Cancer 39 (3): 359-65, 2003. [PUBMED A bstract]
35. Waber DP, Carpentieri SC, Klar N, et al.: Cognitive sequelae in children treated for acute
lymphoblastic leukemia with dexamethasone or prednisone. J Pediatr Hematol Oncol 22 (3): 206-
13, 2000 May-Jun. [PUBMED A bstract]
36. Kadan-Lottick NS, Brouwers P, Breiger D, et al.: A comparison of neurocognitive functioning in

children previously randomized to dexamethasone or prednisone in the treatment of childhood
acute lymphoblastic leukemia. Blood 114 (9): 1746-52, 2009. [PUBMED A bstract]
37. Stubberfield TG, Byrne GC, Jones TW: Growth and growth hormone secretion after treatment for
acute lymphoblastic leukemia in childhood. 18-Gy versus 24-Gy cranial irradiation. J Pediatr
Hematol Oncol 17 (2): 167-71, 1995. [PUBMED A bstract]
38. Rowland JH, Glidewell OJ, Sibley RF, et al.: Effects of different forms of central nervous system
prophylaxis on neuropsychologic function in childhood leukemia. J Clin Oncol 2 (12): 1327-35,
39. Halberg FE, Kramer JH, Moore IM, et al.: Prophylactic cranial irradiation dose effects on late
cognitive function in children treated for acute lymphoblastic leukemia. Int J Radiat Oncol Biol
Phys 22 (1): 13-6, 1992. [PUBMED A bstract]
40. Hill JM, Kornblith AB, Jones D, et al.: A comparative study of the long term psychosocial
functioning of childhood acute lymphoblastic leukemia survivors treated by intrathecal
methotrexate with or without cranial radiation. Cancer 82 (1): 208-18, 1998. [PUBMED A bstract]
41. Pui CH, Cheng C, Leung W, et al.: Extended follow-up of long-term survivors of childhood acute
42. Jankovic M, Brouwers P, Valsecchi MG, et al.: Association of 1800 cGy cranial irradiation with
intellectual function in children with acute lymphoblastic leukaemia. ISPACC. International Study
Group on Psychosocial Aspects of Childhood Cancer. Lancet 344 (8917): 224-7, 1994. [PUBMED
A bstract]
43. Sklar C, Mertens A, Walter A, et al.: Final height after treatment for childhood acute lymphoblastic
leukemia: comparison of no cranial irradiation with 1800 and 2400 centigrays of cranial
irradiation. J Pediatr 123 (1): 59-64, 1993. [PUBMED A bstract]
44. Christie D, Leiper AD, Chessells JM, et al.: Intellectual performance after presymptomatic cranial
radiotherapy for leukaemia: effects of age and sex. Arch Dis Child 73 (2): 136-40, 1995. [PUBMED
A bstract]
45. Waber DP, Tarbell NJ, Kahn CM, et al.: The relationship of sex and treatment modality to
neuropsychologic outcome in childhood acute lymphoblastic leukemia. J Clin Oncol 10 (5): 810-7,
46. Waber DP, Shapiro BL, Carpentieri SC, et al.: Excellent therapeutic efficacy and minimal late
neurotoxicity in children treated with 18 grays of cranial radiation therapy for high-risk acute
lymphoblastic leukemia: a 7-year follow-up study of the Dana-Farber Cancer Institute Consortium
Protocol 87-01. Cancer 92 (1): 15-22, 2001. [PUBMED A bstract]
47. Waber DP, Silverman LB, Catania L, et al.: Outcomes of a randomized trial of hyperfractionated
cranial radiation therapy for treatment of high-risk acute lymphoblastic leukemia: therapeutic
efficacy and neurotoxicity. J Clin Oncol 22 (13): 2701-7, 2004. [PUBMED A bstract]
48. Lning L, Zimmermann M, Reiter A, et al.: Secondary neoplasms subsequent to Berlin-Frankfurt-

Mnster therapy of acute lymphoblastic leukemia in childhood: significantly lower risk without
cranial radiotherapy. Blood 95 (9): 2770-5, 2000. [PUBMED A bstract]
49. Bhatia S, Sather HN, Pabustan OB, et al.: Low incidence of second neoplasms among children
diagnosed with acute lymphoblastic leukemia after 1983. Blood 99 (12): 4257-64, 2002. [PUBMED
A bstract]
50. Filley CM, Kleinschmidt-DeMasters BK: Toxic leukoencephalopathy. N Engl J Med 345 (6): 425-
Postinduction Treatment for Specific ALL Subgroups
T-Cell ALL
Historically, patients with T-cell acute lymphoblastic leukemia (ALL) have had a worse prognosis than
children with precursor B-cell ALL. With current treatment regimens, outcomes for children with T-cell
ALL are now approaching those achieved for children with precursor B-cell ALL. For example, the 10-
year overall survival (OS) for children with T-cell ALL treated on the Dana-Farber Cancer Institute (DFCI)
DFCI-95001 (NCT00004034) trial was 90.1% compared with 88.7% for patients with B-cell disease.[1]
However, in a review of a large number of patients treated on COG trials over a 15-year period, T-cell
immunophenotype still proved to be a negative prognostic factor on multivariate analysis.[2]
T reatment options
1. Protocols of the former Pediatric Oncology Group (POG) treated children with T-cell ALL
differently from children with B-lineage ALL. The POG-9404 protocol for patients with T-cell ALL
was designed to evaluate the role of high-dose methotrexate. The multiagent chemotherapy
regimen for this protocol was based on the DFCI-87001 regimen.[3]
Results of the POG-9404 study indicated that the addition of high-dose methotrexate to the
DFCI-based chemotherapy regimen resulted in significantly improved event-free survival
(EFS) in patients with T-cell ALL (10-year EFS, 78% for those randomly assigned to high-
dose methotrexate versus 68% for those randomly assigned to therapy without high-dose
methotrexate, P = .05).
High-dose methotrexate was associated with a lower incidence of relapses involving the
central nervous system (CNS).[4] This POG study was the first clinical trial to provide
evidence that high-dose methotrexate can improve outcome for children with T-cell ALL.
High-dose asparaginase, doxorubicin, and prophylactic cranial irradiation were also
important components of this regimen.[1,4]
2. Protocols of the former Childrens Cancer Group (CCG) treated children with T-cell ALL on the
same treatment regimens as children with precursor B-cell ALL, basing protocol and treatment
assignment on the patients' clinical characteristics (e.g., age and white blood cell [WBC] count) and
the disease response to initial therapy. Most children with T-cell ALL meet National Cancer
Institute (NCI) high-risk criteria.
Results from CCG-1961 for high-risk ALL including T-cell ALL showed that an augmented
Berlin-Frankfurt-Mnster (BFM) regimen with a single delayed intensification course
produced the best results for patients with morphologic rapid response to initial induction
therapy (estimated 5-year EFS, 83%).[5,6] Almost 60% of events in this group, however,
were isolated CNS relapses.
Overall results from POG-9404 and CCG-1961 were similar, although POG-9404 used
cranial radiation for every patient, while CCG-1961 used cranial radiation only for patients
with slow morphologic response.[6,4]
Among children with NCI standard-risk T-cell ALL, the EFS for those treated on CCG-1952
and COG-1991 studies was inferior to the EFS for those treated on the POG-9404 study.[7]
3. In the Children's Oncology Group (COG), children with T-cell ALL are not treated on the same
protocols as children with precursor B-cell ALL. Pilot studies from the COG have demonstrated the
feasibility of incorporating nelarabine (a nucleoside analog with demonstrated activity in patients
with relapsed and refractory T-cell lymphoblastic disease) [8,9] in the context of a BFM regimen
for patients with newly diagnosed T-cell ALL. The pilot study showed a 5-year EFS rate of 73% for
all patients receiving nelarabine and 69% for those patients with a slow early response.[10]
4. The role of prophylactic cranial radiation in the treatment of T-cell ALL is controversial. Some
groups, such as St. Jude Children's Research Hospital (SJCRH) and the Dutch Childhood Oncology
Group (DCOG), do not use cranial radiation in first-line treatment of ALL, while other groups, such
as DFCI, COG, and BFM, use radiation for the majority of patients with T-cell ALL.
T reatment options under clinical evaluation for T -cell ALL
Treatment options under clinical evaluation for T-cell ALL include the following:

With Newly Diagnosed T-Cell ALL or T-cell Lymphoblastic Lymphoma):
COG-AALL0434 is a phase III trial utilizing a modified augmented BFM regimen for patients aged 1
to 30 years with T-cell ALL. Patients are classified into one of three risk groups (low, intermediate,
or high) based on NCI age/leukocyte criteria, CNS status at diagnosis, morphologic marrow
response on days 15 and 29, and minimal residual disease (MRD) level at day 29. The objectives of
the trial include the following:
To determine the safety and efficacy of adding nelarabine to the modified augmented BFM
regimen in high- and intermediate-risk patients.
To determine the relative safety and efficacy of high-dose (5 g/m2 ) versus Capizzi escalating
lower-dose methotrexate without rescue plus PEG-asparaginase during interim maintenance.
To test the efficacy of treating NCI standard-risk T-cell ALL patients, without CNS disease,
who are rapid responders (about 15% of patients) without cranial radiation.
2. DFCI-11-001 (NCT 01574274) (SC-PEG Asparaginase versus Oncaspar in Pediatric ALL and
Lymphoblastic Lymphoma):
Patients with T-cell ALL are eligible to enroll on a DFCI ALL Consortium protocol that is comparing
the pharmacokinetics and toxicity of two forms of intravenous PEG-L-asparaginase (pegaspargase
[Oncaspar] and calaspargase pegol [SC-PEG]). Patients will be randomly assigned to receive a single
dose of one of these preparations during multiagent induction, and then either pegaspargase every
2 weeks (15 doses total) or calaspargase pegol every 3 weeks (10 doses total) during the 30-week
consolidation phase.
This protocol is also testing whether antibiotic prophylaxis (with fluoroquinolones) reduces rates
of bacteremia and other serious bacterial infections during the remission induction phase. All T-cell
patients are treated on the high-risk arm of this trial, regardless of other presenting characteristics.
Current Clinical T rials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with T-
cell childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by
Infants With ALL
Infant ALL is uncommon, representing approximately 2% to 4% of cases of childhood ALL.[11] Because

of their distinctive biological characteristics and their high risk of leukemia recurrence, infants with ALL
are treated on protocols specifically designed for this patient population. Common therapeutic themes of
the intensive chemotherapy regimens used to treat infants with ALL are the inclusion of postinduction
intensification courses with high doses of cytarabine and methotrexate.[12-14] Despite intensification of
therapy, long-term EFS rates remain below 50%. Infants with congenital leukemia (diagnosed within 1
month of birth) have a particularly poor outcome (17% OS).[15][Level of evidence: 2A]
For infants with MLL gene rearrangement, the EFS rates continue to be in the 17% to 40% range.
[12,13,15-17][Level of evidence: 2A] Factors predicting poor outcome for infants with MLL translocations
include the following:[13]; [18][Level of evidence: 3iDii]
A very young age (<6 months).
Extremely high presenting leukocyte count (200,000300,000/L).
High levels of MRD at the end of induction and consolidation phases of treatment.
T reatment options for infants with MLL translocations
Infants with MLL gene translocations are generally treated on intensified chemotherapy regimens using
agents not typically incorporated into frontline therapy for older children with ALL. However, despite
these intensified approaches, EFS rates remain poor for these patients.
Evidence (intensified chemotherapy regimens for infants with MLL translocations):
1. The international Interfant clinical trials consortium utilized a cytarabine-intensive chemotherapy

regimen, with increased exposure to both low- and high-dose cytarabine during the first few months
of therapy, resulting in a 5-year EFS of 37% for infants with MLL translocations.[13]
2. The COG tested intensification of therapy with a regimen including multiple doses of high-dose
methotrexate, cyclophosphamide, and etoposide, resulting in a 5-year EFS of 34%.[12]
The role of allogeneic hematopoietic stem cell transplant (HSCT) during first remission in infants with
MLL gene translocations remains controversial.
Evidence (allogeneic HSCT in first remission for infants with MLL translocations):
1. On a Japanese clinical trial conducted between 1998 and 2002, all infants with MLL-rearrangement
were intended to proceed to allogeneic HSCT from the best available donor (related, unrelated, or
umbilical cord) 3 to 5 months after diagnosis.[19]
The 3-year EFS for all enrolled infants was 44%. This result was due, in part, to the high
frequency of early relapses, even with intensive chemotherapy; of the 41 infants with MLL-
rearrangement on that study who achieved complete remission (CR), 11 infants (27%)
relapsed before proceeding to transplant.
2. In a COG report that included 189 infants treated on CCG or POG infant ALL protocols between
1996 and 2000, there was no difference in EFS between patients who underwent HSCT in first CR
and those who received chemotherapy alone.[20]
3. The Interfant clinical trials group, after adjusting for waiting time to transplantation, also did not
observe any difference in disease-free survival (DFS) in high-risk infants (defined by prednisone
response) with MLL translocations treated on the Interfant-99 trial with either allogeneic HSCT in
first CR or chemotherapy alone.[13]
In a subset analysis from the same trial, allogeneic HSCT in first remission was associated
with a significantly better DFS for infants with MLL translocations who were younger than 6
months at diagnosis and had either a poor response to steroids at day 8 or leukocyte counts
of at least 300,000/L.[21] In this subset, HSCT in first remission was associated with a 64%
reduction in the risk of failure resulting from relapse or death compared with chemotherapy
alone.
T reatment options for infants without MLL translocations
The optimal treatment for infants without MLL translocations also remains unclear.
1. On the Interfant-99 trial, patients without MLL translocations achieved a relatively favorable
outcome with the cytarabine-intensive treatment regimen (4-year EFS was 74%).[13]
2. A favorable outcome for this subset of patients was obtained in a Japanese study using therapy
comparable to that used to treat older children with ALL;[16] however, that study was limited by
small numbers (n = 22) and a highly unusual gender distribution (91% males).
T reatment options under clinical evaluation for infants with ALL
1. Interfant-06 Study Group trial (DCOG-INT ERFANT -06) (Different Therapies in Treating
Infants With Newly Diagnosed Acute Leukemia): The Interfant-06 Study Group is conducting an
international collaborative randomized trial (including sites in the United States) to test whether an
ALL/acute myeloid leukemia hybrid regimen might improve outcomes for infants with MLL-
rearranged ALL. The role of allogeneic transplantation in first remission is also being assessed in
high-risk patients (defined as infants with MLL-rearranged ALL, younger than 6 months, and WBC
>300,000 /L) or poor peripheral blood response to steroid prophase. Infants with MLL-
rearranged ALL with high MRD at end of consolidation phase are also eligible for allogeneic HSCT
in first remission regardless of other presenting features.
2. COG-AALL0631 (Combination Chemotherapy With or Without Lestaurtinib in Treating Infants

With Newly Diagnosed ALL): In this COG study of infant ALL, an FLT3 inhibitor, lestaurtinib, is
being studied in infants with MLL rearrangement. Infants with MLL rearrangement are known to
have a high level of FLT3 mRNA expression and lestaurtinib has been shown to selectively kill
MLL-rearranged ALL cells in vitro and in vivo.[22] This study combines lestaurtinib with intensive
chemotherapy previously utilized in POG-P9407. An initial safety/activity phase has been
completed and the efficacy phase in which children will be randomly assigned to chemotherapy
with or without lestaurtinib is now underway. Infants with germline MLL are nonrandomly assigned
to less-intensive chemotherapy without lestaurtinib.
Adolescents and Young Adults With ALL
Adolescents and young adults with ALL have been recognized as high risk for decades. Outcomes in
almost all studies of treatment are inferior in this age group compared with children younger than 10
years.[23-25] The reasons for this difference include more frequent presentation of adverse prognostic
factors at diagnosis, including the following:
T-cell immunophenotype.
Philadelphia chromosomepositivity (Ph+).
Lower incidence of favorable cytogenetic abnormalities.
In addition to more frequent adverse prognostic factors, patients in this age group have higher rates of
treatment-related mortality [24-27] and non-adherence to therapy.[26,28]
T reatment options
Studies from the United States and France were among the first to identify the difference in outcome
based on treatment regimens.[29] Other studies have confirmed that older adolescent and young adult
patients fare better on pediatric rather than adult regimens.[29-33]; [34][Level of evidence: 2A] These
study results are summarized in Table 3.
Given the relatively favorable outcome that can be obtained in these patients with chemotherapy
regimens used for high-risk pediatric ALL, there is no role for the routine use of allogeneic HSCT for
adolescents and young adults with ALL in first remission.[25]
Evidence (pediatric treatment regimen):
1. Investigators reported on 197 patients aged 16 to 21 years treated on the CCG study (a pediatric
ALL regimen) who showed a 7-year EFS of 63% compared with 124 adolescents and young adults
treated on the Cancer and Leukemia Group B (CALGB) study (an adult ALL regimen) with a 7-year
EFS of 34%.[29]
2. A study from France of patients aged 15 to 20 years and diagnosed between 1993 and 1999
demonstrated superior outcome for patients treated on a pediatric trial (67%; 5-year EFS)
compared with patients treated on an adult trial (41%; 5-year EFS).[35]
3. In the COG high-risk study (CCG-1961), the 5-year EFS rate for 262 patients aged 16 to 21 years was
71.5%.[25][Level of evidence: 1iiDi] For rapid responders randomly assigned to early intensive
postinduction therapy on the augmented intensity arms of this study, the 5-year EFS rate was 82%
(n = 88).
4. The DFCI ALL Consortium reported that a study of 51 adolescents aged 15 to 18 years in a pediatric
trial had a 5-year EFS of 78%.[31]
5. In an SJCRH study, 44 adolescents aged 15 to 18 years had an EFS of approximately 85% 5%.
[24]
6. In a Spanish study, 35 adolescents (aged 1518 years) and 46 young adults (aged 1930 years) with
standard-risk ALL were treated with a pediatric-based regimen.[34][Level of evidence: 2A]
EFS rate was 61%.
The OS rate was 69%.
There were no differences in outcome between adolescents and young adults.
Other studies have confirmed that older adolescent patients and young adults fare better on pediatric
rather than adult regimens (see Table 3).[30,32]; [34][Level of evidence: 2A]
The reason that adolescents and young adults achieve superior outcomes with pediatric regimens is not
known, although possible explanations include the following: [30]
Treatment setting (i.e., site experience in treating ALL).
Adherence to protocol therapy.
The components of protocol therapy.
Table 3. Outcome According to Treatment Protocol for Adolescents and Young Adults
with ALL
Enlarge
Si t e a n d St u dy Gr ou p A dol escen t a n d You n g Medi a n a ge (y ) Su r v i v a l (% )
A du l t Pa t i en t s (No.)
Un i t ed St a t es [2 9 ]
CCG (Pedia t r ic) 197 16 6 7 , OS 7 y
CA LGB (A du lt ) 124 19 46
Fr a n ce [3 5 ]
FRA LLE 9 3 (Pedia t r ic) 77 16 6 7 EFS
LA LA 9 4 1 00 18 41
It a l y [3 6 ]
A EIOP (Pedia t r ic) 150 15 8 0 , OS 2 y
GIMEMA (A du lt ) 95 16 71
Net h er l a n ds [3 7 ]
DCOG (Pedia t r ic) 47 12 7 1 EFS
HOV ON 44 20 38
Sweden [3 8 ]
NOPHO 9 2 (Pedia t r ic) 36 16 7 4 , OS 5 y
A du lt A LL 99 18 39
Un i t ed Ki n gdom [3 2 ]
MRC A LL (Pedia t r ic) 61 1 5 1 7 7 1 , OS 5 y
UKA LL X II (A du lt ) 67 1 5 1 7 56
ALL = acute lym phoblas tic leuk em ia; EFS = event-free s urvival; OS = overall s urvival.
AEIOP = As s ociaz ione Italiana Em atologia Oncologia Pediatrica; CALGB = Cancer and Leuk em ia Group B; CCG =
Children's Cancer Group; DCOG = Dutch Childhood Oncology Group; FRALLE = French Acute Lym phoblas tic Leuk aem ia;
GIMEMA = Gruppo Italiano Malattie e Matologiche dell'Adulto; HOVON = Dutch-Belgian Hem ato-Oncology Cooperative
Group; LALA = France-Belgium Group for Lym phoblas tic Acute Leuk em ia in Adults ; MRC = Medical Res earch Council
(United Kingdom ); NOPHO = Nordic Society for Pediatric Hem atology and Oncology; UKALL = United Kingdom Acute
Lym phoblas tic Leuk aem ia.
Osteonecrosis
Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related
complications, including osteonecrosis, deep venous thromboses, and pancreatitis.[31,39] Before the use
of postinduction intensification for treatment of ALL, osteonecrosis was infrequent. The improvement in
outcome for children and adolescents aged 10 years and older was accompanied by an increased
incidence of osteonecrosis.
The weight-bearing joints are affected in 95% of patients who develop osteonecrosis and operative
interventions are needed for management of symptoms and impaired mobility in more than 40% of cases.
The majority of the cases are diagnosed within the first 2 years of therapy and often the symptoms are
recognized during maintenance.
Evidence (osteonecrosis):
1. In the CCG-1961 high-risk ALL study, alternate-week dosing of dexamethasone was compared with
standard continuous dexamethasone during delayed intensification to see if the osteonecrosis risk
could be reduced.[39]
The median age at symptom onset was 16 years.
The cumulative incidence was higher in adolescents and young adults aged 16 to 21 years
(20% at 5 years) than in those aged 10 to 15 years (9.9%) or in patients aged 1 to 9 years
(1%).
Operative interventions are needed for management of symptoms and impaired mobility in
more than 40% of cases.
The use of alternate-week dosing of dexamethasone as compared with standard continuous

dexamethasone during delayed intensification in CCG-1961 reduced the risk of
osteonecrosis. The greatest impact was seen in females aged 16 to 21 years, who showed the
highest incidence of osteonecrosis with standard therapy containing continuous
dexamethasone; osteonecrosis was reduced with alternate-week dexamethasone
postinduction (57.6% to 5.6%).
T reatment options under clinical evaluation for adolescent and young adult patients with
ALL

With Newly Diagnosed T-Cell ALL or T-cell Lymphoblastic Lymphoma): This is a phase III trial for
patients aged 1 to 30 years with T-cell ALL utilizing a modified augmented BFM regimen. Patients
are classified into one of three risk groups (low, intermediate, or high) based on NCI age/leukocyte
criteria, CNS status at diagnosis, morphologic marrow response on days 15 and 29, and MRD level
at day 29. The following are objectives of the trial: (1) to determine the safety and efficacy of
adding nelarabine to the modified augmented BFM regimen in high- and intermediate-risk patients,
(2) to determine the relative safety and efficacy of high-dose versus Capizzi methotrexate during
interim maintenance, and (3) to test the efficacy of treating low-risk T-cell ALL patients without
cranial radiation.

High-Risk ALL): The COG-AALL1131 protocol for patients with high-risk B-precursor ALL includes
a randomized comparison of triple intrathecal chemotherapy (methotrexate, cytarabine, and
hydrocortisone) with intrathecal methotrexate, with the objective of determining whether triple
intrathecal chemotherapy reduces CNS-relapse rates and improves overall EFS. Patients with very
high-risk disease include those who, at diagnosis:
Are aged 13 years or older.

Have 0.01% or more detectable MRD at end induction.
Have CNS3 disease.
Have iAMP21.
Have severe hypodiploidy, and/or
Have an M3 marrow on day 29 (induction failure).
These patients are eligible for a three-arm study designed to assess the efficacy of either
clofarabine/etoposide/cyclophosphamide versus cyclophosphamide/etoposide versus the
standard cyclophosphamide/thioguanine/cytarabine combination during the consolidation and
late intensification phases.
Philadelphia Chromosomepositive ALL
Philadelphia chromosomepositive (Ph+) ALL is seen in about 3% of pediatric ALL cases, increases in
adolescence, and is seen in 15% to 25% of adults. In the past, this subtype of ALL has been recognized as
extremely difficult to treat with poor outcome. In 2000, an international pediatric leukemia group
reported a 7-year EFS of 25%, with an OS of 36%.[40] In 2010, the same group reported a 7-year EFS of
31% and an overall survival of 44% in Ph+ ALL patients treated without tyrosine kinase inhibitors.[41]
Treatment of this subgroup has evolved from emphasis on aggressive chemotherapy, to bone marrow
transplantation, and currently to combination therapy using chemotherapy plus tyrosine kinase inhibitor.
T reatment options
Pre-tyrosine kinase inhibitor era
Before the use of imatinib mesylate, HSCT from a matched sibling donor was the treatment of choice for
patients with Ph+ ALL.[42-44] Data to support this include a retrospective multigroup analysis of
children and young adults with Ph+ ALL, in which HSCT from a matched sibling donor was associated
with a better outcome than standard (pre-imatinib mesylate) chemotherapy.[40] In this retrospective
analysis, Ph+ ALL patients undergoing HSCT from an unrelated donor had a very poor outcome.
However, in a follow-up study by the same group evaluating outcomes in the subsequent decade (pre-
imatinib mesylate era), transplantation with matched-related or matched-unrelated donors were
equivalent. DFS at the 5-year time point showed an advantage for transplantation in first remission
compared with chemotherapy that was borderline significant (P = .049), and OS was also higher for
transplantation compared with chemotherapy, although the advantage at 5 years was not significant.[41]
Factors significantly associated with favorable prognosis in the pre-tyrosine kinase inhibitor era included
the following:
Younger age at diagnosis.[41]

Lower leukocyte count at diagnosis.[41]
Early response measures.[41,45,46]
Ph+ ALL with a rapid morphologic response or rapid peripheral blood response to induction
therapy.[41,45]
Following MRD by reverse transcription polymerase chain reaction for the BCR-ABL fusion transcript
may also be useful to help predict outcome for Ph+ patients.[47-49]
T yrosine kinase inhibitor era
Imatinib mesylate is a selective inhibitor of the BCR-ABL protein kinase. Phase I and II studies of single-
agent imatinib in children and adults with relapsed or refractory Ph+ ALL have demonstrated relatively
high response rates, although these responses tended to be of short duration.[50,51]
Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering
imatinib mesylate in combination with multiagent chemotherapy.[52-54] Preliminary outcome of results
for Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.
[55-58]
Evidence (imatinib mesylate):
1. The COG-AALL0031 study evaluated whether imatinib mesylate could be incorporated into an
intensive chemotherapy regimen for children with Ph+ ALL. Patients received imatinib mesylate in
conjunction with chemotherapy during postinduction therapy. Some children proceeded to
allogeneic HSCT after two cycles of consolidation chemotherapy with imatinib mesylate, while
other patients received imatinib mesylate in combination with chemotherapy throughout all
treatment phases.[54]
The 3-year EFS for the 25 patients who received intensive chemotherapy with continuous
dosing of imatinib mesylate is 87.7% 10.9%. These patients fared better than historic
controls treated with chemotherapy alone (without imatinib mesylate), and at least as well as
the other patients on the trial who underwent allogeneic transplantation. Longer follow-up is
necessary to determine whether this novel treatment improves cure rate or merely prolongs
DFS.
2. A nonrandomized study reported the outcome in 16 pediatric patients with Ph+ ALL who were
treated with chemotherapy, imatinib, and allogeneic HSCT.[58]
With a median follow-up of 65 months, the 5-year EFS was 81% for patients who received
imatinib compared with 30% (P = .01) for a historic control group treated similarly, but
without imatinib.[59] Of note, only one of the 16 patients received prophylactic imatinib
posttransplant.
3. The EsPhALL trial tested whether imatinib (administered discontinuously) given in the context of
intensive chemotherapy improves outcome for pediatric Ph+ ALL patients, most of whom (80%)
received an allogeneic HSCT in first CR. Patients were classified as either good risk or poor risk
based on early response measures and remission status at the end of induction. Good- risk patients
(N = 90) were randomly assigned to receive imatinib or not; poor-risk patients (N = 70) were
directly assigned to imatinib. Interpretation of this study is limited due to the high noncompliance
rate with randomized assignment in good-risk patients and early closure before reaching goal
accrual due to publication of the results of the COG AALL1131 trial on which imatinib had been
given continuously with chemotherapy. The overall DFS of patients treated on this trial appeared
to be better than historic controls, and when analyzed as-treated (and not by intent-to-treat), good-
risk patients who received imatinib had a superior DFS. The EsPhALL trial has since been amended
to test continuous dosing of imatinib; results are pending.[60]
Dasatinib, a second-generation inhibitor of tyrosine kinases, is currently being studied in the initial
treatment of Ph+ ALL. Dasatinib has shown significant activity in the CNS, both in a mouse model and a
series of patients with CNS-positive leukemia.[61] The results of a phase I trial of dasatinib in pediatric
patients indicated that once-daily dosing was associated with an acceptable toxicity profile, with few
nonhematologic grade 3 or 4 adverse events.[62]
T reatment options under clinical evaluation for Philadelphia chromosomepositive ALL
1. COG-AALL1122 (NCT 01460160) (Pediatric Ph+ ALL): In this international collaborative

study, patients receive dasatinib, which has increased affinity for BCR/ABL1, in conjunction with a
chemotherapy backbone based on the European EsPhALL regimen. Allogeneic HSCT in first
remission is reserved for those patients with suboptimal early response to therapy, as measured by
morphology and MRD techniques. The goals of this study include the following:
To determine the safety and feasibility of administering dasatinib with this chemotherapy
regimen.
To determine the 3-year EFS of patients treated in this manner.
To compare outcomes with patients treated on prior trials using similar chemotherapy with
imatinib mesylate.
Philadelphia chromosome positive childhood precursor acute lymphoblastic leukemia. The list of clinical
trials can be further narrowed by location, drug, intervention, and other criteria.
References
3. LeClerc JM, Billett AL, Gelber RD, et al.: Treatment of childhood acute lymphoblastic leukemia:
results of Dana-Farber ALL Consortium Protocol 87-01. J Clin Oncol 20 (1): 237-46, 2002.
[PUBMED A bstract]
4. Asselin BL, Devidas M, Wang C, et al.: Effectiveness of high-dose methotrexate in T-cell

lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the
Children's Oncology Group (POG 9404). Blood 118 (4): 874-83, 2011. [PUBMED A bstract]
5. Seibel NL, Asselin BL, Nachman JB, et al.: Treatment of high risk T-cell acute lymphoblastic
leukemia (T-ALL): comparison of recent experience of the Childrens Cancer Group (CCG) and
Pediatric Oncology Group (POG). [Abstract] Blood 104 (11): A-681, 2004.
6. Seibel NL, Steinherz PG, Sather HN, et al.: Early postinduction intensification therapy improves
survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from
the Children's Oncology Group. Blood 111 (5): 2548-55, 2008. [PUBMED A bstract]
7. Matloub Y, Asselin BL, Stork LC, et al.: Outcome of children with T-Cell acute lymphoblastic
leukemia (T-ALL) and standard risk (SR) features: results of CCG-1952, CCG-1991 and POG 9404.
[Abstract] Blood 104 (11): A-680, 195a, 2004.
8. Berg SL, Blaney SM, Devidas M, et al.: Phase II study of nelarabine (compound 506U78) in
children and young adults with refractory T-cell malignancies: a report from the Children's
Oncology Group. J Clin Oncol 23 (15): 3376-82, 2005. [PUBMED A bstract]
9. Kurtzberg J, Ernst TJ, Keating MJ, et al.: Phase I study of 506U78 administered on a consecutive
5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol 23
(15): 3396-403, 2005. [PUBMED A bstract]
10. Dunsmore KP, Devidas M, Linda SB, et al.: Pilot study of nelarabine in combination with intensive
chemotherapy in high-risk T-cell acute lymphoblastic leukemia: a report from the Children's
11. Silverman LB: Acute lymphoblastic leukemia in infancy. Pediatr Blood Cancer 49 (7 Suppl): 1070-
12. Hilden JM, Dinndorf PA, Meerbaum SO, et al.: Analysis of prognostic factors of acute
lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood
108 (2): 441-51, 2006. [PUBMED A bstract]
13. Pieters R, Schrappe M, De Lorenzo P, et al.: A treatment protocol for infants younger than 1 year
with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre
randomised trial. Lancet 370 (9583): 240-50, 2007. [PUBMED A bstract]
14. Silverman LB, McLean TW, Gelber RD, et al.: Intensified therapy for infants with acute
lymphoblastic leukemia: results from the Dana-Farber Cancer Institute Consortium. Cancer 80
(12): 2285-95, 1997. [PUBMED A bstract]
15. van der Linden MH, Valsecchi MG, De Lorenzo P, et al.: Outcome of congenital acute lymphoblastic
leukemia treated on the Interfant-99 protocol. Blood 114 (18): 3764-8, 2009. [PUBMED A bstract]
16. Tomizawa D, Koh K, Sato T, et al.: Outcome of risk-based therapy for infant acute lymphoblastic
leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report
of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group.
17. Biondi A, Rizzari C, Valsecchi MG, et al.: Role of treatment intensification in infants with acute
lymphoblastic leukemia: results of two consecutive AIEOP studies. Haematologica 91 (4): 534-7,
18. Van der Velden VH, Corral L, Valsecchi MG, et al.: Prognostic significance of minimal residual
disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol.
19. Kosaka Y, Koh K, Kinukawa N, et al.: Infant acute lymphoblastic leukemia with MLL gene
rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell
transplantation. Blood 104 (12): 3527-34, 2004. [PUBMED A bstract]
20. Dreyer ZE, Dinndorf PA, Camitta B, et al.: Analysis of the role of hematopoietic stem-cell
transplantation in infants with acute lymphoblastic leukemia in first remission and MLL gene
rearrangements: a report from the Children's Oncology Group. J Clin Oncol 29 (2): 214-22, 2011.
[PUBMED A bstract]
21. Mann G, Attarbaschi A, Schrappe M, et al.: Improved outcome with hematopoietic stem cell
transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-
rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study. Blood 116 (15):
22. Brown P, Levis M, McIntyre E, et al.: Combinations of the FLT3 inhibitor CEP-701 and
chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequence-
dependent manner. Leukemia 20 (8): 1368-76, 2006. [PUBMED A bstract]
23. Nachman J: Clinical characteristics, biologic features and outcome for young adult patients with
acute lymphoblastic leukaemia. Br J Haematol 130 (2): 166-73, 2005. [PUBMED A bstract]
24. Pui CH, Pei D, Campana D, et al.: Improved prognosis for older adolescents with acute
25. Nachman JB, La MK, Hunger SP, et al.: Young adults with acute lymphoblastic leukemia have an
excellent outcome with chemotherapy alone and benefit from intensive postinduction treatment: a
report from the children's oncology group. J Clin Oncol 27 (31): 5189-94, 2009. [PUBMED A bstract]
26. Pichler H, Reismller B, Steiner M, et al.: The inferior prognosis of adolescents with acute
lymphoblastic leukaemia (ALL) is caused by a higher rate of treatment-related mortality and not an
increased relapse rate--a population-based analysis of 25 years of the Austrian ALL-BFM (Berlin-
Frankfurt-Mnster) Study Group. Br J Haematol 161 (4): 556-65, 2013. [PUBMED A bstract]
27. Burke MJ, Gossai N, Wagner JE, et al.: Survival differences between adolescents/young adults and
children with B precursor acute lymphoblastic leukemia after allogeneic hematopoietic cell
transplantation. Biol Blood Marrow Transplant 19 (1): 138-42, 2013. [PUBMED A bstract]
29. Stock W, La M, Sanford B, et al.: What determines the outcomes for adolescents and young adults
with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of
Children's Cancer Group and Cancer and Leukemia Group B studies. Blood 112 (5): 1646-54, 2008.
[PUBMED A bstract]
30. Ramanujachar R, Richards S, Hann I, et al.: Adolescents with acute lymphoblastic leukaemia:
emerging from the shadow of paediatric and adult treatment protocols. Pediatr Blood Cancer 47
(6): 748-56, 2006. [PUBMED A bstract]
31. Barry E, DeAngelo DJ, Neuberg D, et al.: Favorable outcome for adolescents with acute
lymphoblastic leukemia treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia
Consortium Protocols. J Clin Oncol 25 (7): 813-9, 2007. [PUBMED A bstract]
32. Ramanujachar R, Richards S, Hann I, et al.: Adolescents with acute lymphoblastic leukaemia:
outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood
Cancer 48 (3): 254-61, 2007. [PUBMED A bstract]
33. Ram R, Wolach O, Vidal L, et al.: Adolescents and young adults with acute lymphoblastic leukemia
have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-
analysis. Am J Hematol 87 (5): 472-8, 2012. [PUBMED A bstract]
34. Ribera JM, Oriol A, Sanz MA, et al.: Comparison of the results of the treatment of adolescents and
young adults with standard-risk acute lymphoblastic leukemia with the Programa Espaol de
Tratamiento en Hematologa pediatric-based protocol ALL-96. J Clin Oncol 26 (11): 1843-9, 2008.
[PUBMED A bstract]
35. Boissel N, Auclerc MF, Lhritier V, et al.: Should adolescents with acute lymphoblastic leukemia be
treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials.
36. Testi AM, Valsecchi MG, Conter V, et al.: Difference in outcome of adolescents with acute
lymphoblastic leukemia (ALL) enrolled in pediatric (AIEOP) and adult (GIMEMA) protocols.
[Abstract] Blood 104: A-1954, 2004.
37. de Bont JM, van der Holt B, Dekker AW, et al.: [Adolescents with acute lymphatic leukaemia
achieve significantly better results when treated following Dutch paediatric oncology protocols
than with adult protocols]. Ned Tijdschr Geneeskd 149 (8): 400-6, 2005. [PUBMED A bstract]
38. Hallbk H, Gustafsson G, Smedmyr B, et al.: Treatment outcome in young adults and children >10
years of age with acute lymphoblastic leukemia in Sweden: a comparison between a pediatric
protocol and an adult protocol. Cancer 107 (7): 1551-61, 2006. [PUBMED A bstract]
39. Mattano LA Jr, Devidas M, Nachman JB, et al.: Effect of alternate-week versus continuous
dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute
lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial. Lancet Oncol 13 (9):
40. Aric M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia
chromosome-positive acute lymphoblastic leukemia. N Engl J Med 342 (14): 998-1006, 2000.
[PUBMED A bstract]
41. Aric M, Schrappe M, Hunger SP, et al.: Clinical outcome of children with newly diagnosed
Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005.
42. Mori T, Manabe A, Tsuchida M, et al.: Allogeneic bone marrow transplantation in first remission
rescues children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Tokyo
Children's Cancer Study Group (TCCSG) studies L89-12 and L92-13. Med Pediatr Oncol 37 (5):
43. Dombret H, Gabert J, Boiron JM, et al.: Outcome of treatment in adults with Philadelphia
chromosome-positive acute lymphoblastic leukemia--results of the prospective multicenter LALA-
94 trial. Blood 100 (7): 2357-66, 2002. [PUBMED A bstract]
44. Hahn T, Wall D, Camitta B, et al.: The role of cytotoxic therapy with hematopoietic stem cell
transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based

review. Biol Blood Marrow Transplant 11 (11): 823-61, 2005. [PUBMED A bstract]
45. Roy A, Bradburn M, Moorman AV, et al.: Early response to induction is predictive of survival in
childhood Philadelphia chromosome positive acute lymphoblastic leukaemia: results of the
Medical Research Council ALL 97 trial. Br J Haematol 129 (1): 35-44, 2005. [PUBMED A bstract]
46. Schrappe M, Aric M, Harbott J, et al.: Philadelphia chromosome-positive (Ph+) childhood acute
lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable
treatment outcome. Blood 92 (8): 2730-41, 1998. [PUBMED A bstract]
47. Cazzaniga G, Lanciotti M, Rossi V, et al.: Prospective molecular monitoring of BCR/ABL transcript
in children with Ph+ acute lymphoblastic leukaemia unravels differences in treatment response. Br
J Haematol 119 (2): 445-53, 2002. [PUBMED A bstract]
48. Jones LK, Saha V: Philadelphia positive acute lymphoblastic leukaemia of childhood. Br J
Haematol 130 (4): 489-500, 2005. [PUBMED A bstract]
49. Lee S, Kim YJ, Chung NG, et al.: The extent of minimal residual disease reduction after the first 4-
week imatinib therapy determines outcome of allogeneic stem cell transplantation in adults with
Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer 115 (3): 561-70, 2009.
[PUBMED A bstract]
50. Champagne MA, Capdeville R, Krailo M, et al.: Imatinib mesylate (STI571) for treatment of
children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology
Group phase 1 study. Blood 104 (9): 2655-60, 2004. [PUBMED A bstract]
51. Ottmann OG, Druker BJ, Sawyers CL, et al.: A phase 2 study of imatinib in patients with relapsed or
refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100 (6): 1965-71,
52. Thomas DA, Faderl S, Cortes J, et al.: Treatment of Philadelphia chromosome-positive acute
lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 103 (12): 4396-407, 2004.
[PUBMED A bstract]
53. Yanada M, Takeuchi J, Sugiura I, et al.: High complete remission rate and promising outcome by
combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute
lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol
24 (3): 460-6, 2006. [PUBMED A bstract]
54. Schultz KR, Bowman WP, Aledo A, et al.: Improved early event-free survival with imatinib in
Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group
55. Burke MJ, Trotz B, Luo X, et al.: Allo-hematopoietic cell transplantation for Ph chromosome-
positive ALL: impact of imatinib on relapse and survival. Bone Marrow Transplant 43 (2): 107-13,
56. Lee S, Kim YJ, Min CK, et al.: The effect of first-line imatinib interim therapy on the outcome of
allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-
positive acute lymphoblastic leukemia. Blood 105 (9): 3449-57, 2005. [PUBMED A bstract]
57. de Labarthe A, Rousselot P, Huguet-Rigal F, et al.: Imatinib combined with induction or

consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute
lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood 109 (4): 1408-13, 2007.
[PUBMED A bstract]
58. Rives S, Estella J, Gmez P, et al.: Intermediate dose of imatinib in combination with chemotherapy
followed by allogeneic stem cell transplantation improves early outcome in paediatric Philadelphia
chromosome-positive acute lymphoblastic leukaemia (ALL): results of the Spanish Cooperative
Group SHOP studies ALL-94, ALL-99 and ALL-2005. Br J Haematol 154 (5): 600-11, 2011.
[PUBMED A bstract]
59. Rives S, Cams M, Estella J, et al.: Longer follow-up confirms major improvement in outcome in
children and adolescents with Philadelphia chromosome acute lymphoblastic leukaemia treated
with continuous imatinib and haematopoietic stem cell transplantation. Results from the Spanish
Cooperative Study SHOP/ALL-2005. Br J Haematol 162 (3): 419-21, 2013. [PUBMED A bstract]
60. Biondi A, Schrappe M, De Lorenzo P, et al.: Imatinib after induction for treatment of children and
adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a
randomised, open-label, intergroup study. Lancet Oncol 13 (9): 936-45, 2012. [PUBMED A bstract]
61. Porkka K, Koskenvesa P, Lundn T, et al.: Dasatinib crosses the blood-brain barrier and is an
efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood
112 (4): 1005-12, 2008. [PUBMED A bstract]
62. Zwaan CM, Rizzari C, Mechinaud F, et al.: Dasatinib in children and adolescents with relapsed or
refractory leukemia: results of the CA180-018 phase I dose-escalation study of the Innovative
Therapies for Children with Cancer Consortium. J Clin Oncol 31 (19): 2460-8, 2013. [PUBMED
A bstract]
Treatment of Relapsed Childhood ALL
Prognostic Factors After First Relapse of Childhood ALL
The prognosis for a child with acute lymphoblastic leukemia (ALL) whose disease recurs depends on
multiple factors.[1-14]; [15][Level of evidence: 3iiDi]
The two most important prognostic risk factors after first relapse of childhood ALL are the following:
Site of relapse.
Time from diagnosis to relapse.
Other prognostic factors include the following:
Patient characteristics (e.g., age and peripheral blast count at time of relapse).
Risk group classification at initial diagnosis.
Response to reinduction therapy.
Cytogenetics/genomic alterations.
Immunophenotype.
Site of relapse
Patients who have isolated extramedullary relapse fare better than those who have relapse involving the
marrow. In some studies, patients with combined marrow/extramedullary relapse have a better prognosis
than those with a marrow relapse.[5,13]
T ime from diagnosis to relapse
For patients with relapsed B-precursor ALL, early relapses fare worse than later relapses, and marrow
relapses fare worse than isolated extramedullary relapses. For example, survival rates range from less
than 20% for patients with marrow relapses occurring within 18 months from diagnosis to 40% to 50%
for those whose relapses occur more than 36 months from diagnosis.[5,13]
For patients with isolated central nervous system (CNS) relapses, the overall survival (OS) rates for early
relapse (<18 months from diagnosis) are 40% to 50% and 75% to 80% for those with late relapses (>18
months from diagnosis).[13,16] No evidence exists that early detection of relapse by frequent
surveillance (complete blood counts or bone marrow tests) in off-therapy patients improves outcome.[17]
Patient characteristics
Age 10 years and older at diagnosis has been reported as an independent predictor of poor outcome.[13]
A Childrens Oncology Group (COG) study further showed that although patients aged 10 to 15 years at
initial diagnosis do worse than patients aged 1 to 9 years (35% vs. 48%, 3-year postrelapse survival), those
older than age 15 years did much worse (3-year OS, 15%; P = .001).[18]
The Berlin-Frankfurt-Mnster (BFM) group has also reported that high peripheral blast counts (>10,000/
L) at the time of relapse were associated with inferior outcomes in patients with late marrow relapses.
[10]
Children with Down syndrome with relapse of ALL had inferior outcomes as reported in a BFM report
before 2000, primarily due to increased induction deaths and treatment-related mortality. However,
since 2000, with improvements in supportive care, there have been no differences in outcome between
patients with and without Down syndrome.[19]
Risk group classification at initial diagnosis
The COG reported that risk group classification at the time of initial diagnosis was prognostically
significant after relapse; patients who met National Cancer Institute (NCI) standard-risk criteria at initial
diagnosis fared better after relapse than did NCI high-risk patients.[13]
Response to reinduction therapy
Patients with marrow relapses who have persistent morphologic disease at the end of the first month of
reinduction therapy have an extremely poor prognosis, even if they subsequently achieve a second
complete remission (CR2).[20][Level of evidence: 2Di]; [21][Level of evidence: 3iiiA] Several studies
have demonstrated that minimal residual disease (MRD) levels after the achievement of CR2 are of
prognostic significance in relapsed ALL.[20,22-24]; [25][Level of evidence: 3iiiDi] High levels of MRD at
the end of reinduction and at later time points have been correlated with an extremely high risk of
subsequent relapse.
TP53 alterations (mutations and/or copy number alterations) are observed in approximately 11% of
patients with ALL at first relapse and have been associated with an increased likelihood of persistent
leukemia after initial reinduction (38.5% TP53 alteration vs. 12.5% TP53 wild-type) and poor event-free
survival (EFS) (9% TP53 alteration vs. 49% TP53 wild-type). Approximately one-half of the TP53
alterations were present at initial diagnosis and half were newly observed at time of relapse.[26] A second
genomic alteration found to predict for poor prognosis in patients with B-precursor ALL in first bone
marrow relapse is IKZF1 deletion.[27] The frequency of IKZF1 deletion in B-precursor ALL patients at
first relapse patients was 33% in patients in the Acute Lymphoblastic Leukemia Relapse (ALL-REZ) BFM
2002 study, which was approximately twice as high as the frequency described in children at initial
diagnosis of ALL.[27]
Patients with ETV6-RUNX1-positive ALL appear to have a relatively favorable prognosis at first relapse,
consistent with the high percentage of such patients who relapse more than 36 months after diagnosis.
[27,28] In the ALL-REZ BFM 2002 study, an EFS of 84% ( 7%, SE) was observed for patients with ETV6-
RUNX1 ALL with bone marrow relapse.[27] In this study, 94% of patients with ETV6-RUNX1 had a
duration of first remission that extended at least 6 months beyond completion of their primary treatment,
and on multivariate analysis, time to relapse (and not the presence of ETV6-RUNX1) was an independent
predictor of outcome. Similarly, the 5-year OS for ETV6-RUNX1 patients enrolled on the French Acute
Lymphoblastic Leukaemia (FRALLE) 93 study who relapsed at any site more than 36 months after
diagnosis was 81%, and the presence of ETV6-RUNX1 was associated with a favorable survival outcome
compared with other late relapsing patients.[28] However, the 3-year OS of ETV6-RUNX1 patients who
experienced an early relapse (<36 months) was only 31%.
Immunophenotype
Immunophenotype is an important prognostic factor at relapse. Patients with T-cell ALL who experience
a marrow relapse (isolated or combined) at any time during treatment or posttreatment are less likely to
achieve a second remission and long-term EFS than are patients with B-cell ALL.[5,20]
Standard Treatment Options for First Bone Marrow Relapse of Childhood ALL
Standard treatment options for first bone marrow relapse include the following:
1. Reinduction chemotherapy.
2. Postreinduction therapy for patients achieving a CR2.
Reinduction chemotherapy
Initial treatment of relapse consists of reinduction therapy to achieve a CR2. Using either a four-drug
reinduction regimen (similar to that administered to newly diagnosed high-risk patients) or an alternative
regimen including high-dose methotrexate and high-dose cytarabine, approximately 85% of patients with
a marrow relapse achieve a CR2 at the end of the first month of treatment.[5]; [29][Level of evidence: 2A];
[20][Level of evidence: 2Di] Patients with early marrow relapses have a lower rate of achieving a
morphologic CR2 (approximately 70%) than do those with late marrow relapses (approximately 95%).
[20,29]
Evidence (chemotherapy):
1. A COG study used three blocks of intensive reinduction therapy with an initial four-drug
combination including doxorubicin followed by two intensive consolidation blocks before either
hematopoietic stem cell transplantation or chemotherapy continuation.[20]
Second remission was achieved after block 1 in 68% of patients with early relapse (<36
months from initial diagnosis) and in 96% of those with later relapse.
Blocks 2 and 3 reduced MRD in 40 of 56 patients who were MRD-positive after block 1.
2. A United Kingdombased randomized trial of ALL patients in first relapse compared reinduction
with a four-drug combination using idarubicin versus mitoxantrone.[30][Level of evidence: 1iiA]
There was no difference in CR2 rates or end-reinduction MRD levels between the two study
arms.
A significant improvement in OS in the mitoxantrone arm (69% vs. 45%, P = .007) due to
decreased relapse after transplantation was reported.
The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation.
3. Investigators from the ALL-REZ BFM group used a six-drug reinduction approach, including high-
dose methotrexate. A randomized comparison of 1 g/m2 of methotrexate versus 5 g/m2 of
methotrexate with reinduction showed no advantage at the higher dose.[31]
4. The combination of clofarabine, cyclophosphamide, and etoposide was reported to induce

remission in 42% to 56% of patients with refractory or multiply relapsed disease.[32,33]; [34]
[Level of evidence: 2A]
5. The combination of bortezomib plus vincristine, dexamethasone, PEG-L-asparaginase, and

doxorubicin was reported to induce complete response (with or without platelet recovery) in 80%
of multiply relapsed patients with B-precursor ALL.[35][Level of evidence: 3iiiDiv] Notably, this
trial did not include patients who were refractory to reinduction.
6. In a study of induction therapy comprising intensive asparaginase (weekly PEG-L-asparaginase or

12 doses of E.coli asparaginase) with prednisone, vincristine, and doxorubicin for patients with first
relapse, the second complete remission rate was 86% for those receiving PEG-L-asparaginase and
81% for those receiving E.coli asparaginase.[36][Level of evidence: 2Di]
T -cell ALL
Patients with relapsed T-cell ALL have much lower rates of achieving CR2 with standard reinduction
regimens than do patients with B-precursor phenotype.[20] Treatment of children with first relapse of T-
cell ALL in the bone marrow with single-agent therapy using the T-cell selective agent, nelarabine, has
resulted in response rates of approximately 50%.[37] The combination of nelarabine, cyclophosphamide,
and etoposide has produced remissions in patients with relapsed/refractory T-cell ALL.[38]
Postreinduction therapy for patients achieving a second complete remission
Early-relapsing B-precursor ALL
For B-precursor patients with an early marrow relapse, allogeneic transplant from a human leukocyte
antigen (HLA)-identical sibling or matched unrelated donor that is performed in second remission has
been reported in most studies to result in higher leukemia-free survival than a chemotherapy approach.
[7,25,39-47] However, even with transplantation, the survival rate for patients with early marrow relapse
is less than 50%. (Refer to the Hematopoietic Stem Cell Transplantation for First and Subsequent Bone
Marrow Relapse section of this summary for more information.)
Late-relapsing B-precursor ALL
For patients with a late marrow relapse of B-precursor ALL, a primary chemotherapy approach after
achievement of CR2 has resulted in survival rates of approximately 50%, and it is not clear whether
allogeneic transplantation is associated with superior cure rate.[5,9,30,48-50]; [51][Level of evidence:
3iiA] End-reinduction MRD levels may help to identify patients with a high risk of subsequent relapse if
treated with chemotherapy alone (no HSCT) in CR2. Whether transplantation benefits patients with late
marrow relapse but a high level of MRD after reinduction requires further study.
Evidence (MRD-based risk stratification for late-relapse of B-precursor ALL):
1. In a St. Jude Children's Research Hospital study, which included 23 patients with late relapses
treated with chemotherapy in CR2, the 2-year cumulative incidence of relapse was 49% for the 12
patients who were MRD-positive at the end of reinduction and 0% for the 11 patients who were
MRD-negative.[22]
2. In BFM studies, patients are considered to be intermediate risk if they have a late isolated marrow
relapse or an early or late combined marrow/extramedullary relapse. In a study from this group of
61 children with intermediate-risk relapsed B-cell ALL treated with chemotherapy alone in CR2 (no
hematopoietic stem cell transplantation [HSCT]), end-reinduction MRD (assessed by a polymerase
chain reactionbased assay) significantly predicted outcome.[24]
Patients with low MRD (<10-3 ) had a 10-year EFS of 73%, while those with high MRD (>10-3 )
had a 10-year EFS of 10%. On multivariate analysis, end-reinduction MRD was the strongest
independent prognostic factor.
T -cell ALL
For patients with T-cell ALL who achieved remission after bone marrow relapse, outcomes with
postreinduction chemotherapy alone have generally been poor,[5] and these patients are usually treated
with allogeneic HSCT in CR2, regardless of time to relapse.
Standard Treatment for Second and Subsequent Bone Marrow Relapse
Although there are no studies directly comparing chemotherapy with HSCT for patients in third or
subsequent CR, because cure with chemotherapy alone is rare, transplant is generally considered a
reasonable approach for those achieving remission. Long-term survival for all patients after a second
relapse is particularly poor, in the range of less than 10% to 20%.[45] One of the main reasons for this is
failure to obtain a third remission. In spite of numerous attempts at novel combination approaches, only
about 40% of children with second relapse are able to achieve remission.[52] If these patients achieve CR,
HSCT has been shown to cure 20% to 35%, with failures occurring due to high rates of relapse and
transplant-related mortality.[53-57][Level of evidence: 3iiA]
Hematopoietic Stem Cell Transplantation for First and Subsequent Bone

Marrow Relapse
Components of the transplantation process
An updated expert panel review of indications for HSCT has been published.[58] Components of the
transplant process that have been shown to be important in improving or predicting outcome of HSCT for
children with ALL include the following:
1. Total-body irradiation (TBI)-containing transplant preparative regimens.

2. MRD detection just before transplant.

3. Donor type and HLA match.
4. Immune modulation after transplant to prevent relapse.
T BI-containing transplant preparative regimens
For patients proceeding to allogeneic HSCT, TBI appears to be an important component of the
conditioning regimen. Two retrospective studies and a randomized trial suggest that transplant
conditioning regimens that include TBI produce higher cure rates than do chemotherapy-only
preparative regimens.[39,59,60] Fractionated TBI (total dose, 1214 Gy) is often combined with
cyclophosphamide, etoposide, thiotepa, or a combination of these agents. Study findings with these
combinations have generally resulted in similar rates of survival,[61-63] although one study suggested
that if cyclophosphamide is used without other chemotherapy drugs, a dose of TBI in the higher range
may be necessary.[64] Many standard regimens include cyclophosphamide with TBI dosing between 1.32
and 1.4 Gy. On the other hand, when cyclophosphamide and etoposide were used with TBI, doses above
1.2 Gy resulted in worse survival due to excessive toxicity.[62]
MRD detection just before transplant
Disease status at the time of transplantation has long been known to be an important predictor of
outcome, with patients not in CR at HSCT having very poor survival rates.[65] Several studies have also
demonstrated that the level of MRD at the time of transplant is a key risk factor in children with ALL in CR
undergoing allogeneic HSCT.[23,66-70][Level of evidence: 3iiA] Survival rates of patients who are MRD-
positive pretransplant have been reported between 20% and 47%, compared with 60% to 88% in patients
who are MRD-negative.
When patients have received two to three cycles of chemotherapy in an attempt to achieve an MRD-
negative remission, the benefit of further intensive therapy for achieving MRD negativity must be
weighed against the potential for significant toxicity. In addition, there is not clear evidence showing that
MRD positivity in a patient who has received multiple cycles of therapy is a biological disease marker for
poor outcome that cannot be modified, or whether further intervention bringing such patients into an
MRD negative remission will overcome this risk factor and improve survival. Several study groups are
attempting to answer this question.
Donor type and HLA match
Survival rates after matched unrelated donor and umbilical cord blood transplantations have improved
significantly over the past decade and offer an outcome similar to that obtained with matched sibling
donor transplants.[43,71-74]; [75][Level of evidence: 2A]; [76][Level of evidence: 3iiiA]; [77][Level of
evidence: 3iiiDii] Rates of clinically extensive graft-versus-host disease (GVHD) and treatment-related
mortality remain higher after unrelated donor transplantation compared with matched sibling donor
transplants.[44,53,71] However, there is some evidence that matched unrelated donor transplantation
may yield a lower relapse rate, and National Marrow Donor Program and Center for International Blood
and Marrow Transplant Research (CIBMTR) analyses have demonstrated that rates of GVHD, treatment-
related mortality, and OS have improved over time.[78]; [79,80][Level of evidence: 3iiA]
Another CIBMTR study suggests that outcome after one or two antigen mismatched cord blood
transplants may be equivalent to that for a matched family donor or a matched unrelated donor.[81] In
certain cases in which no suitable donor is found or an immediate transplant is considered crucial, a
haploidentical transplant utilizing large doses of stem cells may be considered.[82] For T cell-depleted
CD34-selected haploidentical transplants in which a parent is the donor, patients receiving maternal stem
cells may have a better outcome than those who receive paternal stem cells.[83][Level of evidence: 3iiA]
Immune modulation after transplant to prevent relapse
A number of approaches to prevent relapse after transplantation have been studied, including withdrawal
of immune suppression or donor lymphocyte infusion and targeted immunotherapies, such as monoclonal
antibodies and natural killer cell therapy.[84,85] Trials in Europe and the United States have shown that
patients defined as having a high risk of relapse based upon increasing recipient chimerism (i.e., increased
percentage of recipient DNA markers) can successfully undergo withdrawal of immune suppression
without excessive toxicity.[86] One study showed that in 46 patients with increasing recipient chimerism,
the 31 patients who underwent immune suppression withdrawal, donor lymphocyte infusion, or both
therapies had a 3-year EFS of 37% versus 0% in the nonintervention group (P < .001).[87]
Intrathecal medication after HSCT to prevent relapse
The use of post-HSCT intrathecal chemotherapy chemoprophylaxis is controversial.[88-91]
Relapse after allogeneic HSCT for relapsed ALL
For patients relapsing after an allogeneic HSCT for ALL, a second ablative allogeneic HSCT may be
feasible. However, many patients will be unable to undergo a second HSCT procedure because of failure
to achieve remission, early toxic death, or severe organ toxicity related to salvage chemotherapy.[92]
Among the highly selected group of patients able to undergo a second ablative allogeneic HSCT,
approximately 10% to 30% may achieve long-term EFS.[92-94]; [57,95][Level of evidence: 3iiA]
Prognosis is more favorable in patients with longer duration of remission after the first HSCT and in
patients with CR at the time of the second HSCT.[93,94,96] In addition, one study showed an
improvement in survival after second HSCT if acute GVHD occurred, especially if it had not occurred
after the first transplant.[97]
Reduced-intensity approaches can also cure a percentage of patients when used as a second allogeneic
transplant approach, but only if patients achieve a CR confirmed by flow cytometry.[98][Level of
evidence: 2A] Donor leukocyte infusion has limited benefit for patients with ALL who relapse after
allogeneic HSCT.[99]; [100][Level of evidence: 3iiiA]
Whether a second allogeneic transplant is necessary to treat isolated CNS and testicular relapse is
unknown, and a small series has shown survival in selected patients using chemotherapy alone or
chemotherapy followed by a second transplant.[101][Level of evidence: 3iA]
Treatment of Isolated Extramedullary Relapse
With improved success in treating children with ALL, the incidence of isolated extramedullary relapse has
decreased. The incidence of isolated CNS relapse is less than 5%, and testicular relapse is less than 1% to
2%.[102-104] As with bone marrow and mixed relapses, time from initial diagnosis to relapse is a key
prognostic factor in isolated extramedullary relapses.[105] In addition, age older than 6 years at diagnosis
was noted to be an adverse prognostic factor for patients with an isolated extramedullary relapse in one
study.[106] Of note, in the majority of children with isolated extramedullary relapses, submicroscopic
marrow disease can be demonstrated using sensitive molecular techniques,[107] and successful treatment
strategies must effectively control both local and systemic disease. Patients with an isolated CNS relapse
who show greater than 0.01% MRD in a morphologically normal marrow have a worse prognosis (5-year
EFS, 30%) than do patients with either no MRD or MRD less than 0.01% (5-year EFS, 60%).[107]
CNS relapse
Standard treatment options for childhood ALL that has recurred in the CNS include the following:
1. Systemic and intrathecal chemotherapy.
2. Cranial or craniospinal radiation.
While the prognosis for children with isolated CNS relapse had been quite poor in the past, aggressive
systemic and intrathecal therapy followed by cranial or craniospinal radiation has improved the outlook,
particularly for patients who did not receive cranial radiation during their first remission.
[16,105,108,109]
Evidence (chemotherapy and radiation therapy):
1. In a Pediatric Oncology Group (POG) study using this strategy, children who had not previously
received radiation therapy and whose initial remission was 18 months or longer had a 4-year EFS
rate of approximately 80%, compared with EFS rates of approximately 45% for children with CNS
relapse within 18 months of diagnosis.[105]
2. In a follow-up POG study, children who had not previously received radiation therapy and who had
initial remission of 18 months or more were treated with intensive systemic and intrathecal
chemotherapy for 1 year followed by 18 Gy of cranial radiation only.[16] The 4-year EFS was 78%.
Children with an initial remission of less than 18 months also received the same chemotherapy but
had craniospinal radiation (24 Gy cranial/15 Gy spinal) as in the first POG study and achieved a 4-
year EFS of 52%.
A number of case series describing HSCT in the treatment of isolated CNS relapse have been published.
[110,111] The use of transplantation to treat isolated CNS relapse occurring less than 18 months from
diagnosis, especially T-cell CNS relapse, requires further study.
Evidence (HSCT):
1. In a study comparing outcome of patients treated with either HLA-matched sibling transplants or
chemoradiation therapy as in the POG studies above, 8-year probabilities of leukemia-free survival
adjusted for age and duration of first remission were similar (58% and 66%, respectively).[112]
[Level of evidence: 3iiiDii] This retrospective, registry-based study included transplantation of
both early (<18 months from diagnosis) and late relapses.
Because of the relatively good outcome of patients with isolated CNS relapse more than 18
months from diagnosis treated with chemoradiation therapy alone (>75%), transplantation is
generally not recommended for this group.
T esticular relapse
The results of treatment of isolated testicular relapse depend on the timing of the relapse. The 3-year EFS
of boys with overt testicular relapse during therapy is approximately 40%; it is approximately 85% for
boys with late testicular relapse.[113]
Standard treatment options in North America for childhood ALL that has recurred in the testes include
the following:
1. Chemotherapy.
2. Radiation therapy.
The standard approach for treating isolated testicular relapse in North America is to administer intensive
chemotherapy that includes high-dose methotrexate.[114] Patients who do not respond with a CR after
induction also receive local radiation therapy.
In some European clinical trial groups, orchiectomy of the involved testicle is performed instead of
radiation. Biopsy of the other testicle is performed at the time of relapse to determine if additional local
control (surgical removal or radiation) is to be performed. A study that looked at testicular biopsy at the
end of frontline therapy failed to demonstrate a survival benefit for patients with early detection of occult
disease.[115] While there are limited clinical data concerning outcome without the use of radiation
therapy or orchiectomy, the use of chemotherapy (e.g., high-dose methotrexate) that may be able to
achieve antileukemic levels in the testes is being tested in clinical trials.
Evidence (treatment of testicular relapse [case reports]):
1. Dutch investigators treated five boys with a late testicular relapse with high-dose methotrexate
during induction (12 g/m2 ) and at regular intervals during the remainder of therapy (6 g/m2 )
without testicular radiation. All five boys were long-term survivors.[114]
2. In a small series of boys who had an isolated testicular relapse after a HSCT for a prior systemic
relapse of ALL, five of seven boys had extended EFS without a second HSCT.[101][Level of
evidence: 3iA]
Treatment Options Under Clinical Evaluation for Relapsed Childhood ALL
T rials for ALL in first relapse
1. T ACL 2008-002 (NCT 00981799) (Trial of Nelarabine, Etoposide, and Cyclophosphamide in

Relapsed T-cell ALL and T-cell Lymphoblastic Lymphoma): This trial, conducted by the
Therapeutic Advances in Childhood Leukemia & Lymphoma clinical trials group, is testing the
feasibility of administering nelarabine in combination with cyclophosphamide and etoposide as
reinduction for patients with T-cell ALL in first relapse (as well as those who failed primary
induction therapy). Doses of nelarabine and cyclophosphamide will be escalated in successive
cohorts of patients to determine the maximum tolerated doses of these drugs when given in
combination.
2. DFCI-11-237 (NCT 01523977) (Everolimus With Multiagent Reinduction Chemotherapy in

Pediatric Patients With ALL): Patients in first relapse are eligible to enroll on a Dana-Farber Cancer
Institute ALL Consortium trial testing the feasibility of administering everolimus, an oral mTOR
inhibitor, in combination with multiagent reinduction (vincristine, prednisone, doxorubicin,
intravenous PEG-L-asparaginase, and intrathecal chemotherapy).
T rials for ALL in second or subsequent relapse
1. NCT 01471782 (Clinical Study With Blinatumomab in Pediatric and Adolescent Patients With
Relapsed/Refractory B-Precursor ALL): This is a phase I and II trial evaluating the safety and
efficacy of blinatumomab, the CD3-CD19binding molecule, in recruiting autologous T-cells to
treat relapsed B-cell ALL.
2. COG-ADVL1114 (NCT 01403415) (Temsirolimus, Dexamethasone, Mitoxantrone

Hydrochloride, Vincristine Sulfate, and Pegaspargase in Treating Young Patients With Relapsed
ALL or Non-Hodgkin Lymphoma [NHL]): This is a phase I trial to determine the feasibility and
safety of adding three doses of temsirolimus (intravenously) to the United Kingdom ALL R3
induction regimen for patients with relapsed ALL and NHL.
Multiple clinical trials investigating new agents and new combinations of agents are available for children
with second or subsequent relapsed or refractory ALL and should be considered. These trials are testing
targeted treatments specific for ALL, including monoclonal antibodybased therapies and drugs that
inhibit signal transduction pathways required for leukemia cell growth and survival.
recurrent childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by
References
1. Reismller B, Attarbaschi A, Peters C, et al.: Long-term outcome of initially homogenously treated

and relapsed childhood acute lymphoblastic leukaemia in Austria--a population-based report of the
Austrian Berlin-Frankfurt-Mnster (BFM) Study Group. Br J Haematol 144 (4): 559-70, 2009.
[PUBMED A bstract]
2. Uderzo C, Conter V, Dini G, et al.: Treatment of childhood acute lymphoblastic leukemia after the
first relapse: curative strategies. Haematologica 86 (1): 1-7, 2001. [PUBMED A bstract]
3. Chessells JM, Veys P, Kempski H, et al.: Long-term follow-up of relapsed childhood acute
lymphoblastic leukaemia. Br J Haematol 123 (3): 396-405, 2003. [PUBMED A bstract]
4. Rivera GK, Zhou Y, Hancock ML, et al.: Bone marrow recurrence after initial intensive treatment
for childhood acute lymphoblastic leukemia. Cancer 103 (2): 368-76, 2005. [PUBMED A bstract]
5. Einsiedel HG, von Stackelberg A, Hartmann R, et al.: Long-term outcome in children with relapsed
ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study
of the Berlin-Frankfurt-Mnster Group 87. J Clin Oncol 23 (31): 7942-50, 2005. [PUBMED A bstract]
6. Schroeder H, Garwicz S, Kristinsson J, et al.: Outcome after first relapse in children with acute
lymphoblastic leukemia: a population-based study of 315 patients from the Nordic Society of
Pediatric Hematology and Oncology (NOPHO). Med Pediatr Oncol 25 (5): 372-8, 1995. [PUBMED
A bstract]
7. Wheeler K, Richards S, Bailey C, et al.: Comparison of bone marrow transplant and chemotherapy
for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALL X experience. Medical
Research Council Working Party on Childhood Leukaemia. Br J Haematol 101 (1): 94-103, 1998.
[PUBMED A bstract]
8. Buchanan GR, Rivera GK, Pollock BH, et al.: Alternating drug pairs with or without periodic
reinduction in children with acute lymphoblastic leukemia in second bone marrow remission: a
Pediatric Oncology Group Study. Cancer 88 (5): 1166-74, 2000. [PUBMED A bstract]
9. Rivera GK, Hudson MM, Liu Q, et al.: Effectiveness of intensified rotational combination
chemotherapy for late hematologic relapse of childhood acute lymphoblastic leukemia. Blood 88
(3): 831-7, 1996. [PUBMED A bstract]
10. Bhrer C, Hartmann R, Fengler R, et al.: Peripheral blast counts at diagnosis of late isolated bone
marrow relapse of childhood acute lymphoblastic leukemia predict response to salvage
chemotherapy and outcome. Berlin-Frankfurt-Mnster Relapse Study Group. J Clin Oncol 14 (10):
11. Roy A, Cargill A, Love S, et al.: Outcome after first relapse in childhood acute lymphoblastic
leukaemia - lessons from the United Kingdom R2 trial. Br J Haematol 130 (1): 67-75, 2005.
[PUBMED A bstract]
12. Rizzari C, Valsecchi MG, Aric M, et al.: Outcome of very late relapse in children with acute
lymphoblastic leukemia. Haematologica 89 (4): 427-34, 2004. [PUBMED A bstract]
13. Nguyen K, Devidas M, Cheng SC, et al.: Factors influencing survival after relapse from acute
lymphoblastic leukemia: a Children's Oncology Group study. Leukemia 22 (12): 2142-50, 2008.
[PUBMED A bstract]
14. Locatelli F, Schrappe M, Bernardo ME, et al.: How I treat relapsed childhood acute lymphoblastic
15. Malempati S, Gaynon PS, Sather H, et al.: Outcome after relapse among children with standard-risk
acute lymphoblastic leukemia: Children's Oncology Group study CCG-1952. J Clin Oncol 25 (36):
16. Barredo JC, Devidas M, Lauer SJ, et al.: Isolated CNS relapse of acute lymphoblastic leukemia
treated with intensive systemic chemotherapy and delayed CNS radiation: a pediatric oncology
group study. J Clin Oncol 24 (19): 3142-9, 2006. [PUBMED A bstract]
17. Rubnitz JE, Hijiya N, Zhou Y, et al.: Lack of benefit of early detection of relapse after completion of
therapy for acute lymphoblastic leukemia. Pediatr Blood Cancer 44 (2): 138-41, 2005. [PUBMED
A bstract]
18. Freyer DR, Devidas M, La M, et al.: Postrelapse survival in childhood acute lymphoblastic leukemia
is independent of initial treatment intensity: a report from the Children's Oncology Group. Blood
117 (11): 3010-5, 2011. [PUBMED A bstract]
19. Meyr F, Escherich G, Mann G, et al.: Outcomes of treatment for relapsed acute lymphoblastic
leukaemia in children with Down syndrome. Br J Haematol 162 (1): 98-106, 2013. [PUBMED A bstract]
20. Raetz EA, Borowitz MJ, Devidas M, et al.: Reinduction platform for children with first marrow
relapse in acute lymphoblastic lymphoma. J Clin Oncol 26 (24): 3971-8, 2008. [PUBMED A bstract]
21. von Stackelberg A, Vlzke E, Khl JS, et al.: Outcome of children and adolescents with relapsed
acute lymphoblastic leukaemia and non-response to salvage protocol therapy: a retrospective
analysis of the ALL-REZ BFM Study Group. Eur J Cancer 47 (1): 90-7, 2011. [PUBMED A bstract]
22. Coustan-Smith E, Gajjar A, Hijiya N, et al.: Clinical significance of minimal residual disease in
childhood acute lymphoblastic leukemia after first relapse. Leukemia 18 (3): 499-504, 2004.
[PUBMED A bstract]
23. Sramkova L, Muzikova K, Fronkova E, et al.: Detectable minimal residual disease before allogeneic
hematopoietic stem cell transplantation predicts extremely poor prognosis in children with acute
lymphoblastic leukemia. Pediatr Blood Cancer 48 (1): 93-100, 2007. [PUBMED A bstract]
24. Eckert C, von Stackelberg A, Seeger K, et al.: Minimal residual disease after induction is the
strongest predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia -
long-term results of trial ALL-REZ BFM P95/96. Eur J Cancer 49 (6): 1346-55, 2013. [PUBMED
A bstract]
25. Paganin M, Zecca M, Fabbri G, et al.: Minimal residual disease is an important predictive factor of
outcome in children with relapsed 'high-risk' acute lymphoblastic leukemia. Leukemia 22 (12):
26. Hof J, Krentz S, van Schewick C, et al.: Mutations and deletions of the TP53 gene predict
nonresponse to treatment and poor outcome in first relapse of childhood acute lymphoblastic
leukemia. J Clin Oncol 29 (23): 3185-93, 2011. [PUBMED A bstract]
27. Krentz S, Hof J, Mendioroz A, et al.: Prognostic value of genetic alterations in children with first
bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia. Leukemia 27 (2):
28. Gandemer V, Chevret S, Petit A, et al.: Excellent prognosis of late relapses of ETV6/RUNX1-
positive childhood acute lymphoblastic leukemia: lessons from the FRALLE 93 protocol.
29. Tallen G, Ratei R, Mann G, et al.: Long-term outcome in children with relapsed acute lymphoblastic
leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug
chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol 28 (14): 2339-47, 2010. [PUBMED
A bstract]
30. Parker C, Waters R, Leighton C, et al.: Effect of mitoxantrone on outcome of children with first
relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet 376
(9757): 2009-17, 2010. [PUBMED A bstract]
31. von Stackelberg A, Hartmann R, Bhrer C, et al.: High-dose compared with intermediate-dose
methotrexate in children with a first relapse of acute lymphoblastic leukemia. Blood 111 (5): 2573-
32. Locatelli F, Testi AM, Bernardo ME, et al.: Clofarabine, cyclophosphamide and etoposide as single-
course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic
leukaemia. Br J Haematol 147 (3): 371-8, 2009. [PUBMED A bstract]
33. Miano M, Pistorio A, Putti MC, et al.: Clofarabine, cyclophosphamide and etoposide for the
treatment of relapsed or resistant acute leukemia in pediatric patients. Leuk Lymphoma 53 (9):
34. Hijiya N, Thomson B, Isakoff MS, et al.: Phase 2 trial of clofarabine in combination with etoposide
and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic
35. Messinger YH, Gaynon PS, Sposto R, et al.: Bortezomib with chemotherapy is highly active in
advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood
Leukemia & Lymphoma (TACL) Study. Blood 120 (2): 285-90, 2012. [PUBMED A bstract]
36. Kelly ME, Lu X, Devidas M, et al.: Treatment of relapsed precursor-B acute lymphoblastic leukemia
with intensive chemotherapy: POG (Pediatric Oncology Group) study 9411 (SIMAL 9). J Pediatr
Hematol Oncol 35 (7): 509-13, 2013. [PUBMED A bstract]
37. Berg SL, Blaney SM, Devidas M, et al.: Phase II study of nelarabine (compound 506U78) in
children and young adults with refractory T-cell malignancies: a report from the Children's
38. Commander LA, Seif AE, Insogna IG, et al.: Salvage therapy with nelarabine, etoposide, and
cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and
lymphoma. Br J Haematol 150 (3): 345-51, 2010. [PUBMED A bstract]
39. Eapen M, Raetz E, Zhang MJ, et al.: Outcomes after HLA-matched sibling transplantation or
chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a
collaborative study of the Children's Oncology Group and the Center for International Blood and
Marrow Transplant Research. Blood 107 (12): 4961-7, 2006. [PUBMED A bstract]
40. Barrett AJ, Horowitz MM, Pollock BH, et al.: Bone marrow transplants from HLA-identical siblings
as compared with chemotherapy for children with acute lymphoblastic leukemia in a second
remission. N Engl J Med 331 (19): 1253-8, 1994. [PUBMED A bstract]
41. Uderzo C, Valsecchi MG, Bacigalupo A, et al.: Treatment of childhood acute lymphoblastic
leukemia in second remission with allogeneic bone marrow transplantation and chemotherapy: ten-
year experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric
Hematology Oncology Association. J Clin Oncol 13 (2): 352-8, 1995. [PUBMED A bstract]
42. Harrison G, Richards S, Lawson S, et al.: Comparison of allogeneic transplant versus chemotherapy
for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. MRC Childhood
Leukaemia Working Party. Ann Oncol 11 (8): 999-1006, 2000. [PUBMED A bstract]
43. Bunin N, Carston M, Wall D, et al.: Unrelated marrow transplantation for children with acute
lymphoblastic leukemia in second remission. Blood 99 (9): 3151-7, 2002. [PUBMED A bstract]
44. Borgmann A, von Stackelberg A, Hartmann R, et al.: Unrelated donor stem cell transplantation
compared with chemotherapy for children with acute lymphoblastic leukemia in a second
remission: a matched-pair analysis. Blood 101 (10): 3835-9, 2003. [PUBMED A bstract]
45. Saarinen-Pihkala UM, Heilmann C, Winiarski J, et al.: Pathways through relapses and deaths of
children with acute lymphoblastic leukemia: role of allogeneic stem-cell transplantation in Nordic
data. J Clin Oncol 24 (36): 5750-62, 2006. [PUBMED A bstract]
46. Thomson B, Park JR, Felgenhauer J, et al.: Toxicity and efficacy of intensive chemotherapy for
children with acute lymphoblastic leukemia (ALL) after first bone marrow or extramedullary
relapse. Pediatr Blood Cancer 43 (5): 571-9, 2004. [PUBMED A bstract]
47. Hahn T, Wall D, Camitta B, et al.: The role of cytotoxic therapy with hematopoietic stem cell
transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based
review. Biol Blood Marrow Transplant 11 (11): 823-61, 2005. [PUBMED A bstract]
48. Borgmann A, Baumgarten E, Schmid H, et al.: Allogeneic bone marrow transplantation for a subset
of children with acute lymphoblastic leukemia in third remission: a conceivable alternative? Bone
Marrow Transplant 20 (11): 939-44, 1997. [PUBMED A bstract]
49. Schroeder H, Gustafsson G, Saarinen-Pihkala UM, et al.: Allogeneic bone marrow transplantation
in second remission of childhood acute lymphoblastic leukemia: a population-based case control
study from the Nordic countries. Bone Marrow Transplant 23 (6): 555-60, 1999. [PUBMED A bstract]
50. van den Berg H, de Groot-Kruseman HA, Damen-Korbijn CM, et al.: Outcome after first relapse in
children with acute lymphoblastic leukemia: a report based on the Dutch Childhood Oncology
Group (DCOG) relapse all 98 protocol. Pediatr Blood Cancer 57 (2): 210-6, 2011. [PUBMED A bstract]
51. Beck JC, Cao Q, Trotz B, et al.: Allogeneic hematopoietic cell transplantation outcomes for children
with B-precursor acute lymphoblastic leukemia and early or late BM relapse. Bone Marrow
Transplant 46 (7): 950-5, 2011. [PUBMED A bstract]
52. Gaynon PS: Childhood acute lymphoblastic leukaemia and relapse. Br J Haematol 131 (5): 579-87,
53. Woolfrey AE, Anasetti C, Storer B, et al.: Factors associated with outcome after unrelated marrow
transplantation for treatment of acute lymphoblastic leukemia in children. Blood 99 (6): 2002-8,
54. Afify Z, Hunt L, Green A, et al.: Factors affecting the outcome of stem cell transplantation from
unrelated donors for childhood acute lymphoblastic leukemia in third remission. Bone Marrow
55. Gassas A, Ishaqi MK, Afzal S, et al.: Outcome of haematopoietic stem cell transplantation for
paediatric acute lymphoblastic leukaemia in third complete remission: a vital role for graft-versus-
host-disease/ graft-versus-leukaemia effect in survival. Br J Haematol 140 (1): 86-9, 2008.
[PUBMED A bstract]
56. Nemecek ER, Ellis K, He W, et al.: Outcome of myeloablative conditioning and unrelated donor
hematopoietic cell transplantation for childhood acute lymphoblastic leukemia in third remission.
Biol Blood Marrow Transplant 17 (12): 1833-40, 2011. [PUBMED A bstract]
57. Kato M, Horikoshi Y, Okamoto Y, et al.: Second allogeneic hematopoietic SCT for relapsed ALL in
children. Bone Marrow Transplant 47 (10): 1307-11, 2012. [PUBMED A bstract]
58. Oliansky DM, Camitta B, Gaynon P, et al.: Role of cytotoxic therapy with hematopoietic stem cell
transplantation in the treatment of pediatric acute lymphoblastic leukemia: update of the 2005
evidence-based review. Biol Blood Marrow Transplant 18 (4): 505-22, 2012. [PUBMED A bstract]
59. Davies SM, Ramsay NK, Klein JP, et al.: Comparison of preparative regimens in transplants for
children with acute lymphoblastic leukemia. J Clin Oncol 18 (2): 340-7, 2000. [PUBMED A bstract]
60. Bunin N, Aplenc R, Kamani N, et al.: Randomized trial of busulfan vs total body irradiation
containing conditioning regimens for children with acute lymphoblastic leukemia: a Pediatric Blood
and Marrow Transplant Consortium study. Bone Marrow Transplant 32 (6): 543-8, 2003. [PUBMED
A bstract]
61. Gassas A, Sung L, Saunders EF, et al.: Comparative outcome of hematopoietic stem cell
transplantation for pediatric acute lymphoblastic leukemia following cyclophosphamide and total
body irradiation or VP16 and total body irradiation conditioning regimens. Bone Marrow
62. Tracey J, Zhang MJ, Thiel E, et al.: Transplantation conditioning regimens and outcomes after
allogeneic hematopoietic cell transplantation in children and adolescents with acute lymphoblastic
leukemia. Biol Blood Marrow Transplant 19 (2): 255-9, 2013. [PUBMED A bstract]
63. Bakr M, Rasheed W, Mohamed SY, et al.: Allogeneic hematopoietic stem cell transplantation in
adolescent and adult patients with high-risk T cell acute lymphoblastic leukemia. Biol Blood
64. Marks DI, Forman SJ, Blume KG, et al.: A comparison of cyclophosphamide and total body
irradiation with etoposide and total body irradiation as conditioning regimens for patients
undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete
remission. Biol Blood Marrow Transplant 12 (4): 438-53, 2006. [PUBMED A bstract]
65. Duval M, Klein JP, He W, et al.: Hematopoietic stem-cell transplantation for acute leukemia in
relapse or primary induction failure. J Clin Oncol 28 (23): 3730-8, 2010. [PUBMED A bstract]
66. Goulden N, Bader P, Van Der Velden V, et al.: Minimal residual disease prior to stem cell transplant
for childhood acute lymphoblastic leukaemia. Br J Haematol 122 (1): 24-9, 2003. [PUBMED A bstract]
67. Bader P, Kreyenberg H, Henze GH, et al.: Prognostic value of minimal residual disease
quantification before allogeneic stem-cell transplantation in relapsed childhood acute
lymphoblastic leukemia: the ALL-REZ BFM Study Group. J Clin Oncol 27 (3): 377-84, 2009.
[PUBMED A bstract]
68. Leung W, Pui CH, Coustan-Smith E, et al.: Detectable minimal residual disease before
hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-
high-risk leukemia. Blood 120 (2): 468-72, 2012. [PUBMED A bstract]
69. Ruggeri A, Michel G, Dalle JH, et al.: Impact of pretransplant minimal residual disease after cord
blood transplantation for childhood acute lymphoblastic leukemia in remission: an Eurocord,
PDWP-EBMT analysis. Leukemia 26 (12): 2455-61, 2012. [PUBMED A bstract]
70. Bachanova V, Burke MJ, Yohe S, et al.: Unrelated cord blood transplantation in adult and pediatric
acute lymphoblastic leukemia: effect of minimal residual disease on relapse and survival. Biol
Blood Marrow Transplant 18 (6): 963-8, 2012. [PUBMED A bstract]
71. Locatelli F, Zecca M, Messina C, et al.: Improvement over time in outcome for children with acute
lymphoblastic leukemia in second remission given hematopoietic stem cell transplantation from
unrelated donors. Leukemia 16 (11): 2228-37, 2002. [PUBMED A bstract]
72. Saarinen-Pihkala UM, Gustafsson G, Ringdn O, et al.: No disadvantage in outcome of using

matched unrelated donors as compared with matched sibling donors for bone marrow
transplantation in children with acute lymphoblastic leukemia in second remission. J Clin Oncol 19
(14): 3406-14, 2001. [PUBMED A bstract]
73. Muoz A, Diaz-Heredia C, Diaz MA, et al.: Allogeneic hemopoietic stem cell transplantation for
childhood acute lymphoblastic leukemia in second complete remission-similar outcomes after
matched related and unrelated donor transplant: a study of the Spanish Working Party for Blood
and Marrow Transplantation in Children (Getmon). Pediatr Hematol Oncol 25 (4): 245-59, 2008.
[PUBMED A bstract]
74. Jacobsohn DA, Hewlett B, Ranalli M, et al.: Outcomes of unrelated cord blood transplants and
allogeneic-related hematopoietic stem cell transplants in children with high-risk acute lymphocytic
leukemia. Bone Marrow Transplant 34 (10): 901-7, 2004. [PUBMED A bstract]
75. Kurtzberg J, Prasad VK, Carter SL, et al.: Results of the Cord Blood Transplantation Study
(COBLT): clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric
patients with hematologic malignancies. Blood 112 (10): 4318-27, 2008. [PUBMED A bstract]
76. Smith AR, Baker KS, Defor TE, et al.: Hematopoietic cell transplantation for children with acute
lymphoblastic leukemia in second complete remission: similar outcomes in recipients of unrelated
marrow and umbilical cord blood versus marrow from HLA matched sibling donors. Biol Blood
77. Zhang MJ, Davies SM, Camitta BM, et al.: Comparison of outcomes after HLA-matched sibling and
unrelated donor transplantation for children with high-risk acute lymphoblastic leukemia. Biol
78. Gassas A, Sung L, Saunders EF, et al.: Graft-versus-leukemia effect in hematopoietic stem cell
transplantation for pediatric acute lymphoblastic leukemia: significantly lower relapse rate in
unrelated transplantations. Bone Marrow Transplant 40 (10): 951-5, 2007. [PUBMED A bstract]
79. MacMillan ML, Davies SM, Nelson GO, et al.: Twenty years of unrelated donor bone marrow
transplantation for pediatric acute leukemia facilitated by the National Marrow Donor Program.
Biol Blood Marrow Transplant 14 (9 Suppl): 16-22, 2008. [PUBMED A bstract]
80. Davies SM, Wang D, Wang T, et al.: Recent decrease in acute graft-versus-host disease in children
with leukemia receiving unrelated donor bone marrow transplants. Biol Blood Marrow Transplant
15 (3): 360-6, 2009. [PUBMED A bstract]
81. Eapen M, Rubinstein P, Zhang MJ, et al.: Outcomes of transplantation of unrelated donor umbilical
cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet 369
(9577): 1947-54, 2007. [PUBMED A bstract]
82. Klingebiel T, Handgretinger R, Lang P, et al.: Haploidentical transplantation for acute

lymphoblastic leukemia in childhood. Blood Rev 18 (3): 181-92, 2004. [PUBMED A bstract]
83. Stern M, Ruggeri L, Mancusi A, et al.: Survival after T cell-depleted haploidentical stem cell
transplantation is improved using the mother as donor. Blood 112 (7): 2990-5, 2008. [PUBMED
A bstract]
84. Pulsipher MA, Bader P, Klingebiel T, et al.: Allogeneic transplantation for pediatric acute
lymphoblastic leukemia: the emerging role of peritransplantation minimal residual
disease/chimerism monitoring and novel chemotherapeutic, molecular, and immune approaches
aimed at preventing relapse. Biol Blood Marrow Transplant 15 (1 Suppl): 62-71, 2008. [PUBMED
A bstract]
85. Lankester AC, Bierings MB, van Wering ER, et al.: Preemptive alloimmune intervention in high-risk
pediatric acute lymphoblastic leukemia patients guided by minimal residual disease level before
stem cell transplantation. Leukemia 24 (8): 1462-9, 2010. [PUBMED A bstract]
86. Horn B, Soni S, Khan S, et al.: Feasibility study of preemptive withdrawal of immunosuppression
based on chimerism testing in children undergoing myeloablative allogeneic transplantation for
hematologic malignancies. Bone Marrow Transplant 43 (6): 469-76, 2009. [PUBMED A bstract]
87. Bader P, Kreyenberg H, Hoelle W, et al.: Increasing mixed chimerism is an important prognostic
factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic
stem-cell transplantation: possible role for pre-emptive immunotherapy? J Clin Oncol 22 (9): 1696-
88. Rubin J, Vettenranta K, Vettenranta J, et al.: Use of intrathecal chemoprophylaxis in children after
SCT and the risk of central nervous system relapse. Bone Marrow Transplant 46 (3): 372-8, 2011.
[PUBMED A bstract]
89. Thompson CB, Sanders JE, Flournoy N, et al.: The risks of central nervous system relapse and
leukoencephalopathy in patients receiving marrow transplants for acute leukemia. Blood 67 (1):
90. Oshima K, Kanda Y, Yamashita T, et al.: Central nervous system relapse of leukemia after
allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 14 (10): 1100-7,
91. Ruutu T, Corradini P, Gratwohl A, et al.: Use of intrathecal prophylaxis in allogeneic

haematopoietic stem cell transplantation for malignant blood diseases: a survey of the European
Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 35 (2): 121-4,
92. Mehta J, Powles R, Treleaven J, et al.: Outcome of acute leukemia relapsing after bone marrow
transplantation: utility of second transplants and adoptive immunotherapy. Bone Marrow
93. Eapen M, Giralt SA, Horowitz MM, et al.: Second transplant for acute and chronic leukemia
relapsing after first HLA-identical sibling transplant. Bone Marrow Transplant 34 (8): 721-7, 2004.
[PUBMED A bstract]
94. Bosi A, Laszlo D, Labopin M, et al.: Second allogeneic bone marrow transplantation in acute
leukemia: results of a survey by the European Cooperative Group for Blood and Marrow
Transplantation. J Clin Oncol 19 (16): 3675-84, 2001. [PUBMED A bstract]
95. Nishikawa T, Inagaki J, Nagatoshi Y, et al.: The second therapeutic trial for children with
hematological malignancies who relapsed after their first allogeneic SCT: long-term outcomes.
Pediatr Transplant 16 (7): 722-8, 2012. [PUBMED A bstract]
96. Bajwa R, Schechter T, Soni S, et al.: Outcome of children who experience disease relapse following
allogeneic hematopoietic SCT for hematologic malignancies. Bone Marrow Transplant 48 (5): 661-
97. Schechter T, Avila L, Frangoul H, et al.: Effect of acute graft-versus-host disease on the outcome of
second allogeneic hematopoietic stem cell transplant in children. Leuk Lymphoma 54 (1): 105-9,
98. Pulsipher MA, Boucher KM, Wall D, et al.: Reduced-intensity allogeneic transplantation in
pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow
Transplant Consortium Study ONC0313. Blood 114 (7): 1429-36, 2009. [PUBMED A bstract]
99. Collins RH Jr, Goldstein S, Giralt S, et al.: Donor leukocyte infusions in acute lymphocytic
leukemia. Bone Marrow Transplant 26 (5): 511-6, 2000. [PUBMED A bstract]
100. Levine JE, Barrett AJ, Zhang MJ, et al.: Donor leukocyte infusions to treat hematologic malignancy
relapse following allo-SCT in a pediatric population. Bone Marrow Transplant 42 (3): 201-5, 2008.
[PUBMED A bstract]
101. Bhadri VA, McGregor MR, Venn NC, et al.: Isolated testicular relapse after allo-SCT in boys with
ALL: outcome without second transplant. Bone Marrow Transplant 45 (2): 397-9, 2010. [PUBMED
A bstract]
A bstract]
105. Ritchey AK, Pollock BH, Lauer SJ, et al.: Improved survival of children with isolated CNS relapse
of acute lymphoblastic leukemia: a pediatric oncology group study . J Clin Oncol 17 (12): 3745-52,
106. Domenech C, Mercier M, Plouvier E, et al.: First isolated extramedullary relapse in children with B-
cell precursor acute lymphoblastic leukaemia: results of the Cooprall-97 study. Eur J Cancer 44
(16): 2461-9, 2008. [PUBMED A bstract]
107. Hagedorn N, Acquaviva C, Fronkova E, et al.: Submicroscopic bone marrow involvement in

isolated extramedullary relapses in childhood acute lymphoblastic leukemia: a more precise
definition of "isolated" and its possible clinical implications, a collaborative study of the Resistant
Disease Committee of the International BFM study group. Blood 110 (12): 4022-9, 2007. [PUBMED
A bstract]
108. Ribeiro RC, Rivera GK, Hudson M, et al.: An intensive re-treatment protocol for children with an
isolated CNS relapse of acute lymphoblastic leukemia. J Clin Oncol 13 (2): 333-8, 1995. [PUBMED
A bstract]
109. Kumar P, Kun LE, Hustu HO, et al.: Survival outcome following isolated central nervous system
relapse treated with additional chemotherapy and craniospinal irradiation in childhood acute
lymphoblastic leukemia. Int J Radiat Oncol Biol Phys 31 (3): 477-83, 1995. [PUBMED A bstract]
110. Yoshihara T, Morimoto A, Kuroda H, et al.: Allogeneic stem cell transplantation in children with
acute lymphoblastic leukemia after isolated central nervous system relapse: our experiences and
review of the literature. Bone Marrow Transplant 37 (1): 25-31, 2006. [PUBMED A bstract]
111. Harker-Murray PD, Thomas AJ, Wagner JE, et al.: Allogeneic hematopoietic cell transplantation in
children with relapsed acute lymphoblastic leukemia isolated to the central nervous system. Biol
112. Eapen M, Zhang MJ, Devidas M, et al.: Outcomes after HLA-matched sibling transplantation or
chemotherapy in children with acute lymphoblastic leukemia in a second remission after an
isolated central nervous system relapse: a collaborative study of the Children's Oncology Group
and the Center for International Blood and Marrow Transplant Research. Leukemia 22 (2): 281-6,
113. Wofford MM, Smith SD, Shuster JJ, et al.: Treatment of occult or late overt testicular relapse in
children with acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol 10 (4):
114. van den Berg H, Langeveld NE, Veenhof CH, et al.: Treatment of isolated testicular recurrence of
acute lymphoblastic leukemia without radiotherapy. Report from the Dutch Late Effects Study
Group. Cancer 79 (11): 2257-62, 1997. [PUBMED A bstract]
115. Trigg ME, Steinherz PG, Chappell R, et al.: Early testicular biopsy in males with acute
lymphoblastic leukemia: lack of impact on subsequent event-free survival. J Pediatr Hematol
Oncol 22 (1): 27-33, 2000 Jan-Feb. [PUBMED A bstract]
Changes to this Summary (05/02/2014)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes
available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is
editorially independent of NCI. The summary reflects an independent review of the literature and does
not represent a policy statement of NCI or NIH. More information about summary policies and the role of
the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ
Summary and PDQ NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed,
evidence-based information about the treatment of childhood acute lymphoblastic leukemia. It is
intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide
formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial
Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an
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The lead reviewers for Childhood Acute Lymphoblastic Leukemia Treatment are:
Robert J. Arceci, MD, PhD (Phoenix Children's Hospital)

Karen J Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
Michael A. Pulsipher, MD (Primary Children's Medical Center)
Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
Lewis B. Silverman, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
Malcolm A. Smith, MD, PhD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the
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These designations are intended to help readers assess the strength of the evidence supporting the use of
specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal
evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ Childhood Acute Lymphoblastic Leukemia Treatment. Bethesda, MD:
National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at:
http://cancer.gov/cancertopics/pdq/treatment/childALL/HealthProfessional. Accessed
<MM/DD/YYYY>.
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National Cancer Institute at the National Institutes of Health

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ)

Health Professional Version

General Information About Childhood Acute Lymphoblastic Leukemia (ALL)

Risk-based Treatment Assignment

Treatment Option Overview for Childhood ALL

Treatment for Newly Diagnosed Childhood ALL

Postinduction Treatment for Childhood ALL

CNS-directed Therapy for Childhood ALL

Postinduction Treatment for Specific ALL Subgroups

Treatment of Relapsed Childhood ALL

Changes to this Summary (05/02/2014)

About This PDQ Summary

Get More Information From NCI

General Information About Childhood Acute Lymphoblastic Leukemia

Primary care physician.

Incidence and Epidemiology

Marrow involvement of acute leukemia as seen by light microscopy is defined as follows:

M1: Fewer than 5% blast cells.

Most patients with acute leukemia present with an M3 marrow.

Risk Factors for Developing ALL

Prenatal exposure to x-rays.

Genetic conditions that include the following:

Inherited genetic polymorphisms.

Inherited genetic polymorphisms

Prenatal origin of childhood ALL

Overall Outcome for ALL

Current Clinical Trials

8. Shah A, Coleman MP: Increasing incidence of childhood leukaemia: a controversy re-examined. Br

9. Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: a

lymphoblastic leukemia. Nat Genet 41 (9): 1001-5, 2009. [PUBMED A bstract]

38. Lausten-Thomsen U, Madsen HO, Vestergaard TR, et al.: Prevalence of t(12;21)[ETV6-RUNX1]-

43. Mricke A, Reiter A, Zimmermann M, et al.: Risk-adjusted therapy of acute lymphoblastic

Risk-based Treatment Assignment

Introduction to Risk-based Treatment

High riskWBC count 50,000/L or greater and/or age 10 years or older.

Patient characteristics affecting prognosis.

Leukemic cell characteristics affecting prognosis.

Response to initial treatment affecting prognosis.

Prognostic Factors Affecting Risk-based Treatment

Patient characteristics affecting prognosis

Patient characteristics affecting prognosis include the following:

2. WBC count at diagnosis.

3. Central nervous system (CNS) involvement at diagnosis.

4. Testicular involvement at diagnosis.

5. Down syndrome (trisomy 21).

1. Infants (younger than 1 year)

Infants with extremely high presenting leukocyte counts.

Infants with a poor response to a prednisone prophase.

Infants with an MLL gene rearrangement.

2. Young children (aged 1 to <10 years)

3. Adolescents and young adults (10 years)

WBC count at diagnosis

CNS involvement at diagnosis

T esticular involvement at diagnosis

Down syndrome (trisomy 21)

Leukemic cell characteristics affecting prognosis

Leukemic cell characteristics affecting prognosis include the following:

The World Health Organization (WHO) classifies ALL as either:[70]

1. Precursor B-cell ALL (WHO B lymphoblastic leukemia)

Before 2008, the WHO classified B lymphoblastic leukemia as precursor-B lymphoblastic

The major subtypes of precursor B-cell ALL are as follows:

Pro-B ALL (CD10 negative and no surface or cytoplasmic Ig)